Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors

ABSTRACT

The present invention provides compounds, including resolved enantiomers, resolved diastereomers, solvates and pharmaceutically acceptable salts thereof, comprising the Formula I: 
     
       
         
         
             
             
         
       
     
     Also provided are methods of using the compounds of this invention as AKT protein kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.

PRIORITY OF INVENTION

This application is a divisional of U.S. patent application Ser. No.11/773,949, filed Jul. 5, 2007, now U.S. Pat. No. 8,063,050 and claimspriority to U.S. Provisional Application No. 60/818,718 that was filedon Jul. 6, 2006, which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel inhibitors of serine/threonine proteinkinases (e.g., AKT and related kinases), pharmaceutical compositionscontaining the inhibitors, and methods for preparing these inhibitors.The inhibitors are useful, for example, for the treatment ofhyperproliferative diseases, such as cancer and inflammation, inmammals.

2. Description of the State of the Art

Protein kinases (PK) are enzymes that catalyze the phosphorylation ofhydroxy groups on tyrosine, serine and threonine residues of proteins bytransfer of the terminal (gamma) phosphate from ATP. Through signaltransduction pathways, these enzymes modulate cell growth,differentiation and proliferation, i.e., virtually all aspects of celllife in one way or another depend on PK activity (Hardie, G. and Hanks,S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, SanDiego, Calif.). Furthermore, abnormal PK activity has been related to ahost of disorders, ranging from relatively non-life threatening diseasessuch as psoriasis to extremely virulent diseases such as glioblastoma(brain cancer). Protein kinases are an important target class fortherapeutic modulation (Cohen, P. (2002) Nature Rev. Drug Discovery1:309).

Significantly, atypical protein phosphorylation and/or expression isoften reported to be one of the causative effects of abnormal cellularproliferation, metastasis and cell survival in cancer. The abnormalregulation and/or expression of various kinases, including Akt, VEGF,ILK, ROCK, p70S6K, Bcl, PKA, PKC, Raf, Src, PDK1, ErbB2, MEK, IKK, Cdk,EGFR, BAD, CHK1, CHK2 and GSK3 amongst numerous others, has beenspecifically implicated in cancer.

Protein kinases include two classes; protein tyrosine kinases (PTK) andserine-threonine kinases (STK). The Protein Kinase B/Akt enzymes are agroup of serine/threonine kinases that are overexpressed in a variety ofhuman tumors. One of the best-characterized targets of the PI3K lipidproducts is the 57 KD serine/threonine protein kinase Akt, downstream ofPI3K in the signal transduction pathway (Hemmings, B. A. (1997) Science275:628; Hay N. (2005) Cancer Cell 8:179-183). Akt is the humanhomologue of the protooncogene v-akt of the acutely transformingretrovirus AKT8. Due to its high sequence homology to protein kinases Aand C, Akt is also called Protein Kinase B (PKB) and Related to A and C(RAC). Three isoforms of Akt are known to exist, namely Akt1, Akt2 andAkt3, which exhibit an overall homology of 80% (Staal, S. P. (1987)Proc. Natl. Acad. Sci. 84:5034; Nakatani, K. (1999) Biochem. Biophys.Res. Commun. 257:906; Li et al (2002) Current Topics in Med. Chem.2:939-971; WO 2005/113762). The Akt isoforms share a common domainorganization that consists of a pleckstrin homology domain at theN-terminus, a kinase catalytic domain, and a short regulatory region atthe C-terminus. In addition, both Akt2 and Akt3 exhibit splice variants.Upon recruitment to the cell membrane by PtdInd(3,4,5)P₃, Akt isphosphorylated (activated) by PDK1 at T308, T309 and T305 for isoformsAkt1 (PKBα), Akt2 (PKBβ) and Akt3 (PKBγ), respectively, and at 5473,S474 and S472 for isoforms Akt1, Akt2 and Akt3, respectively. Suchphosphorylation occurs by an as yet unknown kinase (putatively namedPDK2), although PDK1 (Balendran, A., (1999) Curr. Biol. 9:393),autophosphorylation (Toker, A. (2000) J. Biol. Chem. 275:8271) andintegrin-linked kinase (ILK) (Delcommenne, M. (1998) Proc. Natl. Acad.Sci. USA, 95:11211) have been implicated in this process. Akt activationrequires its phosphorylation on residue Ser 473 in the C-terminalhydrophobic motif (Brodbeck et al (1999) J. Biol. Chem. 274:9133-9136;Coffer et al (1991) Eur. J. Biochem. 201:475-481; Alessi et al (1997)Curr. Biol. 7:261-269). Although monophosphorylation of Akt activatesthe kinase, bis(phosphorylation) is required for maximal kinaseactivity.

Akt is believed to assert its effect on cancer by suppressing apoptosisand enhancing both angiogenesis and proliferation (Toker et al. (2006)Cancer Res. 66(8):3963-3966). Akt is overexpressed in many forms ofhuman cancer including, but not limited to, colon (Zinda et al (2001)Clin. Cancer Res. 7:2475), ovarian (Cheng et al (1992) Proc. Natl. Acad.Sci. USA 89:9267), brain (Haas Kogan et al (1998) Curr. Biol. 8:1195),lung (Brognard et al (2001) Cancer Res. 61:3986), pancreatic (Bellacosaet al (1995) Int. J. Cancer 64:280-285; Cheng et al (1996) Proc. Natl.Acad. Sci. 93:3636-3641), prostate (Graff et al (2000) J. Biol. Chem.275:24500) and gastric carcinomas (Staal et al (1987) Proc. Natl. Acad.Sci. USA 84:5034-5037).

The PI3K/Akt/mammalian target of rapamycin (mTOR) pathway has beenexplored for targeted small molecule inhibitor therapy (Georgakis, G.and Younes, A. (2006) Expert Rev. Anticancer Ther. 6(1):131-140;Granville et al (2006) Clin. Cancer Res. 12(3):679-689). Inhibition ofPI3K/Akt signaling induces apoptosis and inhibits the growth of tumorcells that have elevated Akt levels (Kim et al (2005) Current Opinion inInvestig. Drugs 6(12):1250-1258; Luo et al (2005) Molecular Cancer Ther.4(6):977-986).

The development of kinase inhibitors that target abnormally regulatedpathways and ultimately result in disease is of enormous ethical andcommercial interest to the medical and pharmaceutical community. Acompound that inhibits (1) recruitment of Akt to the cell membrane, (2)activation by PDK1 or PDK2, (3) substrate phosphorylation, or (4) one ofthe downstream targets of Akt could be a valuable anticancer agent,either as a stand-alone therapy or in conjunction with other acceptedprocedures.

United States Patent Application Publication 2005/0130954 disclosesinter alia, a variety of compounds that act as AKT inhibitors. Thecompounds are said to be useful in the treatment of hyperproliferativediseases such as cancer.

SUMMARY OF THE INVENTION

This invention provides novel compounds that inhibit AKT proteinkinases. The compounds of the present invention have utility astherapeutic agents for diseases and conditions that can be treated bythe inhibition of AKT protein kinases.

More specifically, the present invention includes compounds having thegeneral Formula I:

and tautomers, resolved enantiomers, resolved diastereomers, solvates,metabolites, salts and pharmaceutically acceptable prodrugs thereof,wherein R¹, R², R⁵, R¹⁰ and A are as defined herein.

The invention also provides pharmaceutical compositions comprising acompound of Formula I, or an enantiomer, solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof.

In a further aspect, the present invention provides a method of treatingdiseases or medical conditions in a mammal mediated by AKT proteinkinases, comprising administering to said mammal one or more compoundsof Formula I, or an enantiomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof, in an amount effective to treat orprevent said disorder. AKT protein kinase mediated conditions that canbe treated according to the methods of this invention include, but arenot limited to, inflammatory, hyperproliferative, cardiovascular,neurodegenerative, gynecological, and dermatological diseases anddisorders.

In a further aspect, the present invention provides a method ofinhibiting the production of AKT protein kinases in a mammal, whichcomprises administering to said mammal a compound of Formula I, or anenantiomer, solvate, metabolite, or pharmaceutically acceptable salt orprodrug thereof in an amount effective to inhibit production of an AKTprotein kinase.

In a further aspect, the present invention provides methods ofinhibiting the activity of AKT protein kinases, comprising contactingsaid kinase with a compound of Formula I.

The inventive compounds may be used advantageously in combination withother known therapeutic agents. Accordingly, this invention alsoprovides pharmaceutical compositions comprising a compound of Formula Ior an enantiomer, solvate, metabolite, or pharmaceutically acceptablesalt or prodrug thereof, in combination with a second therapeutic agent.

This invention also provides compounds of Formula I and enantiomers,solvates, metabolites, and pharmaceutically acceptable salts andprodrugs thereof for use as medicaments in the treatment of AKT proteinkinase-mediated conditions.

An additional aspect of the invention is the use of a compound ofFormula I, or an enantiomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof, for therapy. In one embodiment, thetherapy comprises the treatment of an AKT protein kinase-mediatedcondition.

This invention further provides kits for the treatment of an AKT proteinkinase-mediated disease or disorder, said kit comprising a compound ofFormula I, or an enantiomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof, a container, and optionally apackage insert or label indicating a treatment. The kits may furthercomprise a second compound or formulation comprising a secondpharmaceutical agent useful for treating said disease or disorder.

This invention further includes methods of preparing, methods ofseparating, and methods of purifying of the compounds of this invention.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification, or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature and similar materials differs from or contradicts thisapplication, including but not limited to defined terms, term usage,described techniques, or the like, this application controls.

DEFINITIONS

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms, wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. Examples ofalkyl groups include, but are not limited to, methyl (Me, —CH₃), ethyl(Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

The term “alkylene” as used herein refers to a linear or branchedsaturated divalent hydrocarbon radical of one to twelve carbon atoms,wherein the alkylene radical may be optionally substituted independentlywith one or more substituents described herein. Examples include, butare not limited to, methylene, ethylene, propylene, 2-methylpropylene,pentylene, and the like.

The term “alkenyl” as used herein refers to a linear or branched-chainmonovalent hydrocarbon radical of two to twelve carbon atoms with atleast one site of unsaturation, i.e., a carbon-carbon, sp² double bond,wherein the alkenyl radical may be optionally substituted independentlywith one or more substituents described herein, and includes radicalshaving “cis” and “trans” orientations, or alternatively, “E” and “Z”orientations. Examples include, but are not limited to, ethylenyl orvinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), 1-propenyl, 1-buten-1-yl,1-buten-2-yl, and the like.

The term “alkynyl” as used herein refers to a linear or branchedmonovalent hydrocarbon radical of two to twelve carbon atoms with atleast one site of unsaturation, i.e., a carbon-carbon, sp triple bond,wherein the alkynyl radical may be optionally substituted independentlywith one or more substituents described herein. Examples include, butare not limited to, ethynyl (—C≡CH) and propynyl (propargyl, —CH₂C≡CH).

The terms “cycloalkyl,” “carbocycle,” “carbocyclyl” and “carbocyclicring” as used herein are used interchangeably and refer to saturated orpartially unsaturated cyclic hydrocarbon radical having from three totwelve carbon atoms. The term “cycloalkyl” includes monocyclic andpolycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, whereinthe polycyclic structures optionally include a saturated or partiallyunsaturated cycloalkyl ring fused to a saturated, partially unsaturatedor aromatic cycloalkyl or heterocyclic ring. Examples of cycloalkylgroups include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and the like. Bicyclic carbocyclesinclude those having 7 to 12 ring atoms arranged, for example, as abicyclo[4,5], [5,5], [5,6] or [6,6] system, or as bridged systems suchas bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, andbicyclo[3.2.2]nonane. The cycloalkyl may be optionally substitutedindependently with one or more substituents described herein.

The term “(C₃-C₆-cycloalkyl)-(CH₂)” includes cyclopropyl-CH₂,cyclopentyl-CH₂, and cyclohexyl-CH₂.

“Aryl” as used herein means a monovalent aromatic hydrocarbon radical of6-20 carbon atoms derived by the removal of one hydrogen atom from asingle carbon atom of a parent aromatic ring system. Aryl includesbicyclic radicals comprising an aromatic ring fused to a saturated,partially unsaturated ring, or aromatic carbocyclic or heterocyclicring. Exemplary aryl groups include, but are not limited to, radicalsderived from benzene, naphthalene, anthracene, biphenyl, indene, indane,1,2-dihydronapthalene, 1,2,3,4-tetrahydronapthalene, and the like. Arylgroups may be optionally substituted independently with one or moresubstituents described herein.

The terms “heterocycle”, “heterocyclyl” and “heterocyclic ring” as usedherein are used interchangeably and refer to a saturated or partiallyunsaturated carbocyclic radical of 3 to 8 ring atoms in which at leastone ring atom is a heteroatom independently selected from nitrogen,oxygen and sulfur, the remaining ring atoms being C, where one or morering atoms may be optionally substituted independently with one or moresubstituents described below. The radical may be a carbon radical orheteroatom radical. The term “heterocycle” includes heterocycloalkoxy.“Heterocyclyl” also includes radicals where heterocycle radicals arefused with a saturated, partially unsaturated, or aromatic carbocyclicor heterocyclic ring. Examples of heterocyclic rings include, but arenot limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl and N-pyridyl ureas. Spiro moieties are also includedwithin the scope of this definition. The heterocycle may be C-attachedor N-attached where such is possible. For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl(N-attached) or imidazol-3-yl (C-attached). Examples of heterocyclicgroups wherein 2 ring carbon atoms are substituted with oxo (═O)moieties are isoindoline-1,3-dionyl and 1,1-dioxo-thiomorpholinyl. Theheterocycle groups herein are optionally substituted independently withone or more substituents described herein.

The term “heteroaryl” as used herein refers to a monovalent aromaticradical of a 5-, 6-, or 7-membered ring and includes fused ring systems(at least one of which is aromatic) of 5-10 atoms containing at leastone heteroatom independently selected from nitrogen, oxygen, and sulfur.Examples of heteroaryl groups include, but are not limited to,pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiromoieties are also included within the scope of this definition.Heteroaryl groups may be optionally substituted independently with oneor more substituents described herein.

By way of example and not limitation, carbon bonded heterocycles andheteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine,position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of apyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole ortetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole orthiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole,position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine,position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5,6, 7, or 8 of an isoquinoline. Further examples of carbon bondedheterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl,6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl,3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles andheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of an isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline. Still moretypically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl,1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

The term “halogen” as used herein means fluoro, chloro, bromo or iodo.

The term “a” as used herein means one or more.

As used herein, the terms “compound of this invention,” “compounds ofthe present invention” and “compounds of Formula I” includes compoundsof Formula I and tautomers, resolved enantiomers, resolveddiastereomers, racemic mixtures, solvates, metabolites, salts (includingpharmaceutically acceptable salts) and pharmaceutically acceptableprodrugs thereof.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, an arylalkyl radical is attached to the structure inquestion by the alkyl group.

AKT Inhibitors

The inventive compounds of Formula I are useful for inhibiting AKTprotein kinases. Such compounds have utility as therapeutic agents fordiseases that can be treated by the inhibition of the AKT protein kinasesignaling pathway and tyrosine and serine/threonine kinase receptorpathways.

In particular, certain compounds of Formula I wherein OR² is OH werefound to be at least 50-fold more selective for AKT versus proteinkinase A (PKA). For example, at least 100-fold, and as a furtherexample, at least 150-fold more selective for AKT versus PKA.Selectivity over PKA is desirable, since PKA is involved in manycellular processes important for the normal function and physiology ofmany cell types. Additionally, inhibition of PKA is not believed tocontribute to the anti-proliferative and pro-apoptotic effects of AKTinhibition. Thus, inhibition of PKA could lead to adverse events notassociated with AKT inhibition without contributing to the diseasemodifying benefits of AKT inhibition.

The compounds of Formula I may also be useful as inhibitors of tyrosinekinases as well as serine and threonine kinases in addition to AKT.

In general, one aspect of the invention includes compounds of theFormula I:

and tautomers, resolved enantiomers, resolved diastereomers, solvates,metabolites, salts and pharmaceutically acceptable prodrugs thereof,wherein:

R¹ is H, Me, Et, vinyl, CF₃, CHF₂ or CH₂F;

R² is H or Me;

R⁵ is H, Me, Et, or CF₃;

A is

G is phenyl optionally substituted by one to four R⁹ groups or a 5-6membered heteroaryl optionally substituted by a halogen;

R⁶ and R⁷ are independently H, OCH₃, (C₃-C₆ cycloalkyl)-(CH₂), (C₃-C₆cycloalkyl)-(CH₂CH₂), V—(CH₂)₀₋₁ wherein V is a 5-6 membered heteroarylhaving from one to two ring heteroatoms independently selected from N, Oand S, W—(CH₂)₁₋₂ wherein W is phenyl optionally substituted with F, Cl,Br, I, OMe, CF₃ or Me, C₃-C₆-cycloalkyl optionally substituted withC₁-C₃ alkyl or O(C₁-C₃ alkyl), hydroxy-(C₃-C₆-cycloalkyl),fluoro-(C₃-C₆-cycloalkyl), CH(CH₃)CH(OH)phenyl, 4-6 membered heterocycleoptionally substituted with F, OH, C₁-C₃-alkyl, cyclopropylmethyl orC(═O)(C₁-C₃ alkyl), or C₁-C₆-alkyl optionally substituted with one ormore groups independently selected from OH, oxo, O(C₁-C₆-alkyl), CN, F,NH₂, NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂, cyclopropyl, phenyl, imidazolyl,piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl, ortetrahydropyranyl,

or R⁶ and R⁷ together with the nitrogen to which they are attached forma 4-7 membered heterocyclic ring, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom OH, halogen, oxo, CF₃, CH₂CF₃, CH₂CH₂OH, O(C₁-C₃ alkyl), C(═O)CH₃,NH₂, NHMe, N(Me)₂, S(O)₂CH₃, cyclopropylmethyl and C₁-C₃ alkyl;

R^(a) and R^(b) are H,

or R^(a) is H, and R^(b) and R⁶ together with the atoms to which theyare attached form a 5-6 membered heterocyclic ring having one or tworing nitrogen atoms;

R^(c) and R^(d) are H or Me,

or R^(c) and R^(d) together with the atom to which they are attachedfrom a cyclopropyl ring;

R⁸ is H, Me, F or OH,

or R⁸ and R⁶ together with the atoms to which they are attached form a5-6 membered heterocyclic ring having one or two ring nitrogen atoms;

each R⁹ is independently halogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,O—(C₁-C₆-alkyl), CF₃, OCF₃, S(C₁-C₆-alkyl), CN, OCH₂-phenyl,CH₂O-phenyl, NH₂, NH—(C₁-C₆-alkyl), N—(C₁-C₆-alkyl)₂, piperidine,pyrrolidine, CH₂F, CHF₂, OCH₂F, OCHF₂, OH, SO₂(C₁-C₆-alkyl), C(O)NH₂,C(O)NH(C₁-C₆-alkyl), and C(O)N(C₁-C₆-alkyl)₂;

R¹⁰ is H or Me; and

m, n and p are independently 0 or 1.

In a further embodiment, the compounds of Formula I include compoundswherein G is phenyl optionally substituted by one to four R⁹ groups; and

R⁶ and R⁷ are independently H, (C₃-C₆ cycloalkyl)-(CH₂), (C₃-C₆cycloalkyl)-(CH₂CH₂), V—(CH₂)₀₋₁ wherein V is a 5-6 membered heteroarylhaving from one to two ring heteroatoms independently selected from N, Oand S, W—(CH₂)₁₋₂ wherein W is phenyl optionally substituted with F, Clor Me, C₃-C₆-cycloalkyl, hydroxy-(C₃-C₆-cycloalkyl),fluoro-(C₃-C₆-cycloalkyl), CH(CH₃)CH(OH)phenyl, or C₁-C₆-alkyloptionally substituted with one or more groups independently selectedfrom OH, O(C₁-C₆-alkyl), CN, F, NH₂, NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂,piperidinyl, and pyrrolidinyl,

or R⁶ and R⁷ together with the nitrogen to which they are attached forma 4-6 membered heterocyclic ring, wherein said heterocyclic ring isoptionally substituted with one or more groups independently selectedfrom OH, halogen, oxo, CF₃, CH₂CF₃, and (C₁-C₃)alkyl;

R^(c) and R^(d) are H or Me;

R⁸ is H, Me, or OH; and

each R⁹ is independently halogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, CF₃,OCF₃, S(C₁-C₆-alkyl), CN, CH₂O-phenyl, NH₂, NH—(C₁-C₆-alkyl),N—(C₁-C₆-alkyl)₂, piperidine, pyrrolidine, CH₂F, CHF₂, OCH₂F, OCHF₂, OH,SO₂(C₁-C₆-alkyl), C(O)NH₂, C(O)NH(C₁-C₆-alkyl), and C(O)N(C₁-C₆-alkyl)₂.

Referring to the G group of Formula I, examples include phenyloptionally substituted with one or more R⁹ groups independently selectedfrom F, Cl, Br, CN, methyl, ethyl, isopropyl, OCH₃, OCH₂CH₃, CF₃, OCF₃,SCH₃, OCH₂Ph and cyclopropyl. Exemplary embodiments include, but are notlimited to, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl,3-bromophenyl, 4-bromophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl,2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl,3-ethoxyphenyl, 4-ethoxyphenyl, 2-thiomethylphenyl, 3-thiomethylphenyl,4-thiomethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 2-cyclopropylphenyl, 3-cyclopropylphenyl,4-cyclopropylphenyl, 4-chloro-3-fluorophenyl, 3,4-difluorophenyl,4-bromo-3-fluorophenyl, 3-fluoro-4-methylphenyl,3-fluoro-4-methoxyphenyl, 3-fluoro-4-trifluoromethylphenyl,4-cyano-3-fluorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl,2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl,3,5-dichlorophenyl. 3,5-difluorophenyl, 3-chloro-5-fluorophenyl,3-chloro-4-fluorophenyl, 3-bromo-4-fluorophenyl,3,5-difluoro-4-chlorophenyl, 2,3-difluoro-4-chlorophenyl,2,5-difluoro-4-chlorophenyl, 3,5-difluoro-4-bromophenyl,2,3-difluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl and4-(OCH₂Ph)-phenyl.

A further example of the G group of Formula I includes when R⁹ is I. Anexemplary embodiment includes 4-iodophenyl.

Referring to the G group of Formula I, the phrase “5-6 memberedheteroaryl optionally substituted by a halogen” includes thiophenes andpyridines optionally substituted by halogens. Particular examplesinclude, but are not limited to, the structures:

Referring to the R⁶ and R⁷ groups of Formula I, the term“(C₃-C₆-cycloalkyl)-(CH₂)” includes cyclopropyl-CH₂, cyclobutyl-CH₂,cyclopentyl-CH₂, and cyclohexyl-CH₂.

Referring to the R⁶ and R⁷ groups of Formula I, the term “V—(CH₂)₀₋₁”includes, but is not limited to, the following structures:

Referring to the R⁶ and R⁷ groups of Formula I, the term“hydroxy-(C₃-C₆-cycloalkyl)” includes, but is not limited to, thefollowing structures:

Referring to the R⁶ and R⁷ groups of Formula I, the term“fluoro-(C₃-C₆-cycloalkyl)” includes but is not limited to, thefollowing structures:

Referring to the R⁶ and R⁷ groups of Formula I, the phrase “C₁-C₆-alkyloptionally substituted with one or more groups independently selectedfrom OH, OMe, and CN” includes, but is not limited to, CH₂OH, CH₂CH₂OH,CH₂CH₂CH₂OH, CH₂CH(OH)CH₂, CH₂CH₂CH(OH)CH₃, CH₂C(OH)(CH₃)₂, CH₂OMe,CH₂CH₂OMe, CH₂CH₂CH₂OMe, CH₂CH(OMe)CH₂, CH₂CH₂CH(OMe)CH₃,CH₂C(OMe)(CH₃)₂, CH₂CN, CH₂CH₂CN, CH₂CH₂CH₂CN, CH₂CH(CN)CH₂,CH₂CH₂CH(CN)CH₃, CH₂C(CN)(CH₃)₂, and the like.

Referring to the R⁶ and R⁷ groups of Formula I, in certain embodimentsthe term “heteroaryl” refers to a 5-6 membered heteroaryl having fromone to two ring heteroatoms independently selected from N, O and S.

Referring to the R⁶ and R⁷ groups of Formula I, in certain embodimentsthe phrase “4-6 membered heterocycle optionally substituted with F, OH,C₁-C₃-alkyl, cyclopropylmethyl or C(═O)(C₁-C₃ alkyl)” refers to a 4-6membered heterocycle having from one to two ring heteroatomsindependently selected from N, O and S, and optionally substituted witha CH₃ or C(═O)CH₃ substituent. Examples include, but are not limited to,the structures:

In one embodiment of Formula I, R¹⁰ is H.

In another embodiment of Formula I, R¹⁰ is methyl.

In one embodiment of Formula I, OR² is in the (S) or (R) configuration.In a particular embodiment, R² is H.

In another embodiment of Formula I, R² is methyl.

In one embodiment of Formula I, R⁵ is H. In another embodiment, R⁵ ismethyl, wherein said methyl is optionally in the (S) configuration.

In one embodiment of Formula I, R¹ is methyl, wherein said methyl isoptionally in the (R) configuration. In another embodiment, R¹ is H.

In one embodiment of Formula I, G is phenyl optionally substituted withone or more groups independently selected from F, Cl, Br, Me, Et,isopropyl, CN, CF₃, OCF₃, SMe, OMe and CH₂OPh. Exemplary embodiments ofG include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-fluorophenyl, 4-bromophenyl, 4-methylphenyl, 4-ethylphenyl,4-isopropylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl,4-methoxyphenyl, 4-ethoxyphenyl, 4-thiomethylphenyl,4-trifluoromethoxyphenyl, 4-cyclopropylphenyl, 4-chloro-3-fluorophenyl,3,4-difluorophenyl, 4-bromo-3-fluorophenyl, 3-fluoro-4-methylphenyl,3-fluoro-4-methoxyphenyl, 3-fluoro-4-trifluoromethylphenyl,4-cyano-3-fluorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl,2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl,3,5-dichlorophenyl. 3,5-difluorophenyl, 3-chloro-5-fluorophenyl,3-chloro-4-fluorophenyl, 3-bromo-4-fluorophenyl,3,5-difluoro-4-chlorophenyl, 2,3-difluoro-4-chlorophenyl,2,5-difluoro-4-chlorophenyl, 3,5-difluoro-4-bromophenyl,2,3-difluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl or4-(OCH₂Ph)-phenyl.

In particular embodiments, G is 4-chlorophenyl, 2,4-dichlorophenyl,3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl,3,4-dichlorophenyl, 3-fluoro-4-bromophenyl, 4-methoxyphenyl,4-fluorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl,4-thiomethylphenyl, or 4-methylphenyl.

In additional embodiments, R⁹ may be I or OCH₂-phenyl.

Additionally, G may be 4-iodophenyl, 4-trifluoromethoxyphenyl,3,5-difluorophenyl, 4-bromo-3-fluorophenyl, 3-fluoro-4-methoxyphenyl,3-fluoro-4-trifluoromethylphenyl, 3-trifluoromethoxy-4-chlorophenyl,3-fluoro-4-trifluoromethoxyphenyl, 3-trifluoromethyl-4-chlorophenyl,3-trifluoromethoxy-4-fluorophenyl, 3,5-bis(trifluoromethyl)phenyl,3-chloro-5-fluorophenyl, 3-bromo-4-methoxyphenyl,2-fluoro-4-chlorophenyl, 2-fluoro-4-bromophenyl,2-fluoro-4-trifluoromethylphenyl, or 3-trifluoromethyl-4-fluorophenyl.

In one embodiment, G may be a 5-6 membered heteroaryl optionallysubstituted by a halogen. In certain embodiments, G is a thiophene orpyridine optionally substituted by a halogen. Particular embodimentsinclude:

In one embodiment, R⁶ or R⁷ may be H.

In one embodiment, R⁶ or R⁷ may be OCH₃.

In one embodiment, R⁶ or R⁷ may be (C₃-C₆ cycloalkyl)-(CH₂).

In one embodiment, R⁶ or R⁷ may be (C₃-C₆ cycloalkyl)-(CH₂CH₂).

In one embodiment, R⁶ or R⁷ may be V—(CH₂)₀₋₁ wherein V is a 5-6membered heteroaryl having from one to two ring heteroatomsindependently selected from N, O and S.

In one embodiment, R⁶ or R⁷ may be W—(CH₂)₁₋₂ wherein W is phenyloptionally substituted with F, Cl, Br, I, OMe, CF₃ or Me.

In one embodiment, R⁶ or R⁷ may be C₃-C₆-cycloalkyl optionallysubstituted with C₁-C₃ alkyl or O(C₁-C₃ alkyl).

In one embodiment, R⁶ or R⁷ may be hydroxy-(C₃-C₆-cycloalkyl).

In one embodiment, R⁶ or R⁷ may be fluoro-(C₃-C₆-cycloalkyl).

In one embodiment, R⁶ or R⁷ may be CH(CH₃)CH(OH)phenyl.

In one embodiment, R⁶ or R⁷ may be 4-6 membered heterocycle optionallysubstituted with F, OH, C₁-C₃ alkyl, cyclopropylmethyl or C(═O)CH₃. Inanother embodiment, R⁶ or R⁷ may be a 4-6 membered heterocycleoptionally substituted with C₁-C₃ alkyl or C(═O)CH₃

In one embodiment, R⁶ or R⁷ may be C₁-C₆-alkyl optionally substitutedwith one or more groups independently selected from OH, oxo,O(C₁-C₆-alkyl), CN, F, NH₂, NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂,cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl,tetrahydrofuranyl, oxetanyl and tetrahydropyranyl. In anotherembodiment, R⁶ or R⁷ may be C₁-C₆-alkyl optionally substituted with oneor more groups independently selected from OH, oxo, O(C₁-C₆-alkyl), CN,F, NH₂, NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂, cyclopropyl, phenyl,imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, andtetrahydropyranyl.

In one embodiment, R⁶ or R⁷ may be H.

In another embodiment, R⁶ or R⁷ may be methyl, ethyl, isopropyl,isobutyl, tert-butyl, 3-pentyl, or CH₂-tBu (neopentyl). In an additionalembodiment, R⁶ or R⁷ may be CH₂CH₂OH, CH₂CH₂OMe, CH₂CH₂CF₃,CH₂CH(CH₃)OH, CH₂CH(CF₃)OH, CH₂CF₃, CH₂CH₂F, CH₂C(═O)NH₂,CH₂C(═O)NH(CH₃), CH₂C(═O)N(CH₃)₂, CH₂C(═O)NH(iPr), CH₂CH₂C(═O)NH₂,CH(phenyl)CH₂OH, CH(tetrahydropyranyl)CH₂OH, CH₂CH₂CH₂(imidazolyl),CH₂CH₂(morpholinyl), CH₂(tetrahydropyranyl), orCH₂CH₂(tetrahydropyranyl) or

In an additional embodiment, R⁶ and R⁷ are independently CH(isopropyl)₂,CH₂CH₂CH₂OH, CH(CH₂CH₂OH)₂, CH(CH₂CH₂OMe)₂, CH₂CH₂CH₂OMe, CH₂CN,CH₂-phenyl.

In another embodiment, R⁶ or R⁷ may be OCH₃.

In another embodiment, R⁶ or R⁷ may be CH₂-cyclopropyl, orCH₂-cyclopentyl. In an additional embodiment, R⁶ or R⁷ may beCH₂-cyclobutyl.

In another embodiment, R⁶ or R⁷ may be CH₂-(pyrid-3-yl). In anadditional embodiment, R⁶ or R⁷ may be CH₂-(pyrid-2-yl) orCH₂-(pyrid-4-yl).

In another embodiment, R⁶ or R⁷ may be cyclopropyl, cyclopentyl,cyclohexyl, 4-methoxycyclohexyl, 4,4-dimethylcyclohexyl,3,3-dimethylcyclohexyl, or 4-hydroxycyclohex-1-yl.

In another embodiment, R⁶ or R⁷ may be CH(CH₃)CH(OH)phenyl.

In another embodiment, R⁶ or R⁷ may be pyrrolidinyl, piperidinyl,tetrahydropyranyl, tetrahydrofuranyl, or

In other embodiments, R⁶ and R⁷ together with the nitrogen to which theyare attached form a 4-7 membered heterocyclic ring, wherein saidheterocyclic ring is optionally substituted with one or more groupsindependently selected from OH, halogen, oxo, CF₃, CH₂CF₃, CH₂CH₂OH,OCH₃, C(═O)CH₃, NH₂, NHMe, N(Me)₂, S(O)₂CH₃, and (C₁-C₃)alkyl.

In particular embodiments, NR⁶R⁷ is selected from the structures:

In another embodiment, NR⁶R⁷ is selected from the structures:

In one embodiment, R⁸ and R⁶ together with the atoms to which they areattached form a 5-6 membered heterocyclic ring having one or two ringnitrogen atoms. In certain embodiments, R⁷ is H.

In another embodiment, R⁸ and R⁶ together with the atoms to which theyare attached form a 5-6 membered heterocyclic ring having one ringnitrogen atom. In certain embodiments, R⁷ is H.

In one embodiment, R^(a) is H, and R^(b) and R⁶ together with the atomsto which they are attached form a 5-6 membered heterocyclic ring havingone or two ring nitrogen atoms. In certain embodiments, R⁷ is H.

In another embodiment, R^(a) is H, and R^(b) and R⁶ together with theatoms to which they are attached form a 5-6 membered heterocyclic ringhaving one ring nitrogen atom. In certain embodiments, R⁷ is H.

In one embodiment of Formula I, m is 1, n is 0, p is 0, such that A isrepresented by the Formula 1:

wherein G, R⁶, R⁷, R⁸, R^(c) and R^(d) are as defined herein.

In certain embodiments of the group A having the Formula 1, R⁸ is H orOH. In certain embodiments, R⁸ is H. In particular embodiments, A hasthe configuration:

In certain embodiments of the A group having the Formula 1, R^(c) andR^(d) are H. In other embodiments, R^(c) and R^(d) together with theatom to which they are attached form a cyclopropyl ring.

In certain embodiments of the A group having the Formula 1, R⁶ and R⁷are independently H, C₃-C₆-cycloalkyl, heteroaryl-(CH₂),hydroxy-(C₃-C₆-cycloalkyl), CH(CH₃)CH(OH)phenyl, or (C₁₋₆)-alkyloptionally substituted with one or more groups independently selectedfrom OH, OMe, and CN. In particular embodiments, R⁶ and R⁷ areindependently H, methyl, ethyl, isopropyl, isobutyl, tert-butyl,3-pentyl, CH(isopropyl)₂, CH₂CH₂OH, CH₂CH₂CH₂OH, CH(CH₂CH₂OH)₂,CH₂CH₂OMe, CH(CH₂CH₂OMe)₂, CH₂CH₂CH₂OMe, CH₂CN, CH₂-cyclopropyl,CH₂-cyclobutyl, CH₂-tBu, cyclopentyl, cyclohexyl, CH₂-phenyl,CH₂-(pyrid-2-yl), CH₂-(pyrid-3-yl), CH₂-(pyrid-4-yl),4-hydroxycyclohex-1-yl, or CH(CH₃)CH(OH)phenyl.

In additional embodiments of the A group having the Formula 1, R⁶ or R⁷may be OCH₃, C₃-C₆-cycloalkyl optionally substituted with OCH₃, 5-6membered heterocycle optionally substituted with CH₃ or C(═O)CH₃, orC₁-C₆-alkyl optionally substituted with one or more groups independentlyselected from OH, oxo, O(C₁-C₆-alkyl), CN, F, NH₂, NH(C₁-C₆-alkyl),N(C₁-C₆-alkyl)₂, cyclopropyl, phenyl, imidazolyl, piperidinyl,pyrrolidinyl, morpholinyl, and tetrahydropyranyl.

In particular embodiments, R⁶ or R⁷ may independently be CH₂CF₃,CH₂CH₂F, CH₂-cyclopentyl, 4-methoxycyclohexyl, 4,4-dimethylcyclohexyl,3,3-dimethylcyclohexyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl,tetrahydrofuranyl,

In particular embodiments of the A group having the Formula 1, NR⁶R⁷ isNH₂, NHMe, NHEt, NHPr, NHiPr, NHtBu, NH(CH₂-tBu), NH(CH₂-cyclopropyl),NH(CH₂-cyclobutyl), NH(cyclopentyl), NH(CH₂-pyridyl), NH(cyclohexyl),NH(3-pentyl), NHCH(isopropyl)₂, NH(CH₂CH₂OH), NH(CH₂CH₂CH₂OH),NH(CH₂CH₂OMe), NH(CH₂CH₂CH₂OMe), NH(CH₂CN), NMe₂, NMeEt, NMePr,NMe(iPr), NMe(CH₂-cyclopropyl), NMe(CH₂-cyclobutyl), NMe(CH₂CH₂OH),NMe(CH₂CH₂CH₂OH), NMe(CH₂CH₂OMe), NMe(CH₂CH₂CH₂OMe), NEt₂, NEtPr,NEt(iPr), NEt(CH₂-cyclopropyl), NEt(CH₂-cyclobutyl), NEt(CH₂CH₂OH),NEt(CH₂CH₂CH₂OH),

In other embodiments of the A group having the Formula 1, R⁶ and R⁷together with the N to which they are attached form a 4-6 memberedheterocyclic ring having a ring nitrogen atom and optionally having asecond ring heteroatom selected form N and O, wherein said heterocyclicring is optionally substituted with one or more groups independentlyselected from OH, halogen, oxo, CH₂CF₃, and (C₁-C₃)alkyl. For example,in certain embodiments, R⁶ and R⁷ together with the N to which they areattached form a pyrrolidinyl, piperidinyl, azetidinyl, morpholinyl orpiperizinyl ring, wherein said pyrrolidinyl, piperidinyl, azetidinyl,morpholinyl and piperazinyl rings are optionally substituted with one ormore groups independently selected from OH, F methyl, CH₂CF₃, and oxo.In particular embodiments of the A group having the Formula 1, NR⁶R⁷ isselected from the structures:

In additional embodiments, R⁶ and R⁷ together with the nitrogen to whichthey are attached form a 4-6 membered heterocyclic ring, wherein saidheterocyclic ring is optionally substituted with one or more groupsindependently selected from OH, halogen, oxo, CF₃, CH₂CF₃, CH₂CH₂OH,OCH₃, C(═O)CH₃, NH₂, NHMe, N(Me)₂, S(O)₂CH₃, and (C₁-C₃)alkyl. In aparticular embodiment, NR⁶R⁷ has the structure:

In certain embodiments of the A group having the Formula 1, R⁶ and R⁸together with the atoms to which they are attached form a 5-6 memberedheterocyclic ring having one or two ring nitrogen atoms. In otherembodiments, R⁶ and R⁸ together with the atoms to which they areattached form a pyrrolidinyl or piperidinyl ring.

In particular embodiments, the A group is selected from the formulas:

In additional embodiments, the A group is selected from the formulas:

In additional embodiments, the A group is selected from the formulas:

In certain embodiments, compounds of the present invention arerepresented by Formula 1B:

wherein G, R⁶ and R⁷ are as defined herein.

In another embodiment of Formula I, m is 1, n is 1, p is 0, such that Ais represented by the Formula 2:

wherein G, R⁶, R⁷, R⁸, R^(c) and R^(d) are as defined herein. In certainembodiments, A has the configuration:

In certain embodiments of the group A having the Formula 2, R⁸ is H orMe.

In certain embodiments of the group A having the Formula 2, R^(c) andR^(d) are methyl. In other embodiments, R^(c) and R^(d) are H.

In certain embodiments, R^(c) and R^(d) together with the atom to whichthey are attached form a cyclopropyl ring.

In certain embodiments of the group A having the Formula 2, R⁶ and R⁷are independently H, methyl, ethyl, propyl, isopropyl, CH₂-cyclopropyl,or CH₂-cyclobutyl,

or R⁶ and R⁷ together with the nitrogen to which they are attached forma pyrrolidinyl, piperidinyl, or azetidinyl ring,

or R⁶ and R⁸ together with the atoms to which they are attached form apiperidinyl or pyrrolidinyl ring.

In additional embodiments of the group A having the Formula 2, R⁶ or R⁷may independently be isobutyl, tetrahydropyranyl, CH(phenyl)CH₂OH,CH(tetrahydropyranyl)CH₂OH, cyclohexyl, CH₂CH₂OH, CH₂CH₂OCH₃,CH₂CH(CH₃)OH, CH₂CH(CF₃)OH, CH₂C(═O)N(CH₃)₂, CH₂C(═O)NH₂,CH₂CH₂CH₂(imidazolyl) or

In certain embodiments of the group A having the Formula 2, NR⁶R⁷ isNH₂, NHMe, NHEt, NHPr, NH(iPr), NH(CH₂-cyclopropyl), NH(CH₂-cyclobutyl),NMe₂, NMeEt, NMePr, NMe(iPr), NEt₂, NEtPr, or NEt(iPr).

In certain embodiments of the group A having the Formula 2, NR⁶R⁷ isNH(isobutyl), NH(CH₂CH₂OH), NH(CH₂CH₂OCH₃), NH(CH₂C(═O)N(CH₃)₂),NH(CH₂CH(CH₃)OH), NH(cyclohexyl), NH(tetrahydropyranyl),NH(CH(phenyl)CH₂OH), NH(CH(tetrahydropyranyl)CH₂OH), NMe(CH₂CH₂OMe),NH(CH₂C(═O)NH₂), NH(CH₂CH₂CH₂(imidazolyl)) or

In other embodiments, NR⁶R⁷ is selected from the structures:

In other embodiments, NR⁶R⁷ is selected from the structures:

In certain embodiments of the group A having the Formula 2, R⁶ and R⁷are H. In particular embodiments, A is selected from:

In additional embodiments, A is selected from:

In certain embodiments, compounds of the present invention arerepresented by Formula 2B:

wherein G, R^(c), R^(d), R⁶ and R⁷ are as defined herein.

In another embodiment of Formula I, m is 1, n is 0 and p is 1, such thatA is represented by the Formula 3:

wherein G, R⁶, R⁷, R⁸, R^(a), R^(b), R^(c) and R^(d) are as definedherein. In certain embodiments, A has the configuration:

In certain embodiments of the group A having the Formula 3, R⁸ is H.

In certain embodiments of the group A of Formula 3, R^(c) and R^(d) areH. In other embodiments, R^(c) and R^(d) together with the atom to whichthey are attached form a cyclopropyl ring.

In certain embodiments of the group A of Formula 3, R⁶ and R⁷ areindependently H, methyl, ethyl, propyl, isopropyl, t-butyl,CH₂-cyclopropyl, or CH₂-cyclobutyl.

In certain embodiments, NR⁶R⁷ of Formula 3 is NH₂, NHMe, NHEt, NHPr,NH(iPr), NHtBu, NH(CH₂-cyclopropyl), or NH(CH₂-cyclobutyl).

In certain embodiments of the group A having the Formula 3, R⁶ and R⁷are H. In particular embodiments, A is:

In other embodiments of group A of Formula 3, R^(a) and R⁸ are H, andR^(b) and R⁶ together with the atoms to which they are attached form a 5to 6 membered heterocyclic ring wherein one of the ring atoms isnitrogen. In certain embodiments, R^(b) and R⁶ together with the atomsto which they are attached form a pyrrolidinyl ring. In certainembodiments, R⁷ is H. In particular embodiments, A is selected from:

In certain embodiments, compounds of the present invention arerepresented by Formula 3B:

wherein G, R⁶ and R⁷ are as defined herein.

In certain embodiments of Formula I, m is 0, n is 0 and p is 1, suchthat A is represented by the Formula 4:

wherein G, R⁶, R⁷, and R⁸ are as defined herein. In certain embodiments,A has the configuration:

In certain embodiments of the group A having the Formula 4, R⁸ is H. Incertain embodiments, R⁶ and R⁷ are independently H or Me. In particularembodiments, A is selected from:

In certain embodiments, R⁶ or R⁷ may be methyl, iPr, piperidinyl,tetrahydrofuranyl, CH₂CH₂CF₃, CH₂CH₂(morpholinyl),CH₂(tetrahydropyranyl), CH₂CH₂(tetrahydropyranyl), CH₂C(═O)NH(iPr),CH₂C(═O)N(Me)₂ or

Additional embodiments of A include:

In certain embodiments, compounds of the present invention arerepresented by Formula 4B:

wherein G and R⁵ are as defined herein.

In certain embodiments, compounds of the present invention arerepresented by Formula 4C:

wherein G and R⁵ are as defined herein.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers anddiastereomers, and mixtures, racemic or otherwise, thereof. Accordingly,this invention also includes all such isomers, including diastereomericmixtures, pure diastereomers and pure enantiomers of the compounds ofthis invention. The term “enantiomer” refers to two stereoisomers of acompound which are non-superimposable mirror images of one another. Theterm “diastereomer” refers to a pair of optical isomers which are notmirror images of one another. Diastereomers have different physicalproperties, e.g. melting points, boiling points, spectral properties,and reactivities.

The compounds of the present invention may also exist in differenttautomeric forms, and all such forms are embraced within the scope ofthe invention. The term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

The compounds of Formula I include solvates, pharmaceutically acceptableprodrugs and salts (including pharmaceutically acceptable salts) of suchcompounds.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically with theother ingredients comprising a formulation, and/or the mammal beingtreated therewith.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.The term “hydrate” can also be used to refer to a complex wherein thesolvent molecule is water.

A “prodrug” is a compound that may be converted under physiologicalconditions or by solvolysis to the specified compound or to a salt ofsuch compound. Prodrugs include compounds wherein an amino acid residue,or a polypeptide chain of two or more (e.g., two, three or four) aminoacid residues, is covalently joined through an amide or ester bond to afree amino, hydroxy or carboxylic acid group of a compound of thepresent invention. The amino acid residues include but are not limitedto the 20 naturally occurring amino acids commonly designated by threeletter symbols and also includes phosphoserine, phosphothreonine,phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine,gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylicacid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of Formula I can be derivatized as an amideor alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups may be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Advanced DrugDelivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and aminogroups are also included, as are carbonate prodrugs, sulfonate estersand sulfate esters of hydroxy groups. Derivatization of hydroxy groupsas (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group maybe an alkyl ester optionally substituted with groups including, but notlimited to, ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem., 1996,39, 10. More specific examples include replacement of the hydrogen atomof the alcohol group with a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylacyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids,P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting fromthe removal of a hydroxyl group of the hemiacetal form of acarbohydrate).

Free amines of compounds of Formula I can also be derivatized as amides,sulfonamides or phosphonamides. All of these moieties may incorporategroups including, but not limited to, ether, amine and carboxylic acidfunctionalities. For example, a prodrug can be formed by the replacementof a hydrogen atom in the amine group with a group such as R-carbonyl,RO-carbonyl, NRR′-carbonyl, wherein R and R′ are each independently(C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, or benzyl, or R-carbonyl is a naturalα-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OYwherein Y is H, (C₁-C₆)alkyl or benzyl, —C(OY₀)Y₁ wherein Y₀ is (C₁-C₄)alkyl and Y₁ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl ormono-N— or di-N,N—(C₁-C₆)alkylaminoalkyl, or —C(Y₂)Y₃ wherein Y₂ is H ormethyl and Y₃ is mono-N— or di-N,N—(C₁-C₆)alkylamino, morpholino,piperidin-1-yl or pyrrolidin-1-yl.

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

Alternatively or additionally, compound of the invention may possess asufficiently acidic group, a sufficiently basic group, or bothfunctional groups, and accordingly react with any of a number ofinorganic or organic bases or acids to form a salt. Examples of saltsinclude those salts prepared by reaction of the compounds of the presentinvention with a mineral or organic acid or an inorganic base, suchsalts including, but not limited to, sulfates, pyrosulfates, bisulfates,sulfites, bisulfites, phosphates, monohydrogenphosphates,dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,bromides, iodides, acetates, propionates, decanoates, caprylates,acrylates, formates, isobutyrates, caproates, heptanoates, propiolates,oxalates, malonates, succinates, suberates, sebacates, fumarates,maleates, butyn-1,4-dioates, hexyne-1,6-dioates, benzoates,chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,methoxybenzoates, phthalates, sulfonates, xylenesulfonates,phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycollates, tartrates, methanesulfonates,propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,and mandelates. Since a single compound of the present invention mayinclude more than one acidic or basic moiety, the compounds of thepresent invention may include mono, di or tri-salts in a singlecompound.

If the inventive compound is a base, the desired salt may be prepared byany suitable method available in the art, for example, by treatment ofthe free base with an acidic compound, for example an inorganic acidsuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as aceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, apyranosidyl acid such as glucuronic acid or galacturonic acid, an alphahydroxy acid such as citric acid or tartaric acid, an amino acid such asaspartic acid or glutamic acid, an aromatic acid such as benzoic acid orcinnamic acid, a sulfonic acid such as p-toluenesulfonic acid orethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired salt may be preparedby any suitable method, for example, by treatment of the free acid withan inorganic or organic base. Examples of suitable inorganic saltsinclude those formed with alkali and alkaline earth metals such aslithium, sodium, potassium, barium and calcium. Examples of suitableorganic base salts include, for example, ammonium, dibenzylammonium,benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium,phenylethylbenzylamine, dibenzylethylenediamine, and the like salts.Other salts of acidic moieties may include, for example, those saltsformed with procaine, quinine and N-methylglucosamine, plus salts formedwith basic amino acids such as glycine, ornithine, histidine,phenylglycine, lysine and arginine.

In certain embodiments, the salt is a “pharmaceutically acceptable salt”which, unless otherwise indicated, includes salts that retain thebiological effectiveness of the corresponding free acid or base of thespecified compound and are not biologically or otherwise undesirable.

The compounds of Formula I also include other salts of such compoundswhich are not necessarily pharmaceutically acceptable salts, and whichmay be useful as intermediates for preparing and/or purifying compoundsof Formula I and/or for separating enantiomers of compounds of FormulaI.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. All isotopes of any particular atom or elementas specified are contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Certain isotopically-labeled compounds of thepresent invention (e.g., those labeled with ³H and ¹⁴C) are useful incompound and/or substrate tissue distribution assays. Tritiated (i.e.,³H) and carbon-14 (i.e., ¹⁴C) isotopes are useful for their ease ofpreparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds of the present invention can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes and/orin the Examples herein below, by substituting an isotopically labeledreagent for a non-isotopically labeled reagent.

Metabolites of Compounds of Formula I

Also falling within the scope of this invention are the in vivometabolic products of compounds of Formula I described herein. A“metabolite” is a pharmacologically active product produced throughmetabolism in the body of a specified compound or salt thereof. Suchproducts may result, for example, from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds of FormulaI, including compounds produced by a process comprising contacting acompound of this invention with a mammal for a period of time sufficientto yield a metabolic product thereof.

Metabolites are identified, for example, by preparing a radiolabelled(e.g., ¹⁴C or ³H) isotope of a compound of the invention, administeringit parenterally in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to ahuman, allowing sufficient time for metabolism to occur (typically about30 seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolites, so long as they are nototherwise found in vivo, are useful in diagnostic assays for therapeuticdosing of the compounds of the invention.

Synthesis of Compounds of Formula I

Compounds of this invention may be synthesized by synthetic routes thatinclude processes analogous to those well known in the chemical arts,particularly in light of the description contained herein. The startingmaterials are generally available from commercial sources such asAldrich Chemicals (Milwaukee, Wis.) or are readily prepared usingmethods well known to those skilled in the art (e.g., prepared bymethods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.), orBeilsteins Handbuch der organischen Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including supplements).

Compounds of Formula I may be prepared singly or as compound librariescomprising at least 2, for example 5 to 1,000 compounds, or 10 to 100compounds. Libraries of compounds of Formula I may be prepared by acombinatorial ‘split and mix’ approach or by multiple parallel synthesesusing either solution phase or solid phase chemistry, by proceduresknown to those skilled in the art. Thus according to a further aspect ofthe invention there is provided a compound library comprising at least 2compounds of Formula I, or salts thereof.

For illustrative purposes, Schemes 1-4 and Schemes A-J shows a generalmethod for preparing the compounds of the present invention as well askey intermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used to synthesizethe inventive compounds. Although specific starting materials andreagents are depicted in the Schemes and discussed below, other startingmaterials and reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Scheme 1 shows a method of preparing compound 10 of Formula I wherein R¹is H, R² is OH and R⁵ is H. Formation of pyrimidine 2 can beaccomplished by the reaction of the keto ester 1 with thiourea in thepresence of a base such as KOH in an appropriate solvent, such asethanol. After reduction of the mercapto group of compound 2 understandard reducing conditions (e.g., Raney N₁ and NH₄OH) to providecompound 3, the hydroxypyrimidine 3 can be chlorinated under standardconditions (e.g., POCl₃ in DIEA/DCE) to provide compound 4. Compound 4is then oxidized under standard conditions (e.g., MCPBA in anappropriate solvent such as CHCl₃) to give the pyrimidine-oxide 5.Treatment of the pyrimidine-oxide with acetic anhydride gives therearrangement product 6. Compound 7 is obtained by reacting compound 6with an appropriately substituted piperidine under standard S_(N)Arreaction conditions to provide compound 7. Compound 7 is hydrolyzed toprovide compound 8, which is then deprotected to yield the intermediate9. Acylation of the piperazinyl cyclopenta[d]pyrimidine 9 with anappropriated amino acid in the presence of a coupling reagent such asHBTU, followed by deprotection if necessary, gives compound 10 ofFormula I.

Scheme 2 shows a method of preparing compounds 22, 25 and 27 of FormulaI wherein R¹, R² and R⁵ are methyl. According to Scheme 2, brominationof (+)-pulegone 11 with bromine gives the dibromide 12. The treatment ofthe dibromide 12 with a base such as sodium ethoxide provides thepulegenate 13. Ozonolysis of the pulegenate 13 gives the ketoester 14.Treatment of the keto ester 14 with thiourea in the presence of a basesuch as KOH in ethanol, followed by reduction of the mercapto groupunder standard conditions (e.g. Raney Ni catalyst in ammonia) affordsthe hydroxypyrimidine 16. Chlorination of the hydroxypyrimidine 16 understandard conditions (e.g., POCl₃) provides the 4-chloropyrimidine 17.The oxidation of the 4-chloropyrimidine 17 with an oxidizing agent suchas MCPBA or hydrogen peroxide provides the N-oxide 18. Rearrangement ofthe N-oxide 18 with acetic anhydride yields the intermediate 19.Compound 19 is reacted with the desired piperazine according to theprocedure described in Scheme 1 to provide compound 20 where R⁵ is H and23 where R⁵ is Me. Compounds 20 and 23 are subjected to chiralseparation using HPLC with chiral stationary and then hydrolyzed upontreatment with a base such as lithium hydroxide to provide compounds 21and 24, respectively. After deprotection, compounds 21 and 24 are thenreacted with the appropriate amino acid to provide compounds 22 and 25,respectively.

Alternatively, the 7-hydroxy group of compound 24 may be alkylated withalkylation reagent such as alkyl halide in the presence of a base suchas NaH or KOH to provide compound 26 where R² is Me. After deprotection,compound 26 is then reacted with the appropriate amino acid to providecompound 27.

Scheme 3 shows an alternative method of preparing compounds 73 and 74.According to Scheme 3, amination of 14 using an ammonia synthon gives63. Pyrimidine formation using, for example, ammonium formate in thepresence of formamide at 50° C.-250° C. and/or at high pressure givesthe bicyclic unit 64. Activation of 64 using, for example, POCl₃ orSOCl₂ gives the activated pyrimidine 65. Displacement of this leavinggroup, using a suitable protected/substituted piperidine at 0° C. to150° C. gives the piperidine 66. Oxidation, using, for example,m-chloroperoxybenzoic acid (“MCPBA” or “m-CPBA”) or Oxone® at −20° C. to50° C. gives the N-oxide 67. Treatment with an acylating agent (eg.acetic anhydride) followed by heating (40° C. to 200° C.) causesrearrangement to give 68. Hydrolysis, using, for example LiOH or NaOH at0° C. to 50° C. gives the alcohol 69. Oxidation, using for example,Swern conditions, MnO₄ or pyridine-SO₃ complex at appropriatetemperatures gives the ketone 70. Asymmetric reduction using, forexample, a catalytic chiral catalyst in the presence of hydrogen, theCBS catalyst or a borohydride reducing agent in the presence of a chiralligand gives rise to either the (R) or the (S) stereochemistry at thealcohol 71 or 72. Alternatively, a non-chiral reducing agent could beused (eg. H₂, Pd/C), allowing the methyl group on the cyclopentane unitto provide facial selectivity and ultimately diastereoselectivity. Ifthe reduction gives a lower diastereoselectivity, the diastereomerscould be separated by (for example) chromatography, crystallization orderivitization. Finally deprotection of the Boc-group, using, forexample, acid at 0° C. to 50° C., acylation using an appropriatelyfunctionalized amino acid and final functionalization of the amine ofthis amino acid (eg. removal of any protecting group, alkylation,reductive amination or acylation to introduce new substituents) givesrise to the final compounds 73 and 74.

Introduction of a chiral auxiliary (e.g. Evans oxazolidinone, etc.) tocompound 1 may be accomplished by standard acylation procedures to givethe conjugate 2. For example, treatment of the acid with an activatingagent (e.g. COCl₂) or mixed anhydride formation (e.g.2,2-dimethylpropanoyl chloride) in the presence of an amine base at −20°C. to 100° C. followed by treatment with the appropriate chiralauxiliary (X) gives compound 2. The stereochemistry and choice of thechiral auxiliary may determine the stereochemistry of the newly createdchiral center and the diastereoselectivity. Treatment of compound 2 witha Lewis acid (eg. TiCl₄) at low temperature (e.g. −20° C. to −100° C.)and an amine base (e.g. Hunig's base) followed by the use of anappropriately substituted imminium ion precursor 3 at low temperaturethen gives rise to compound 4. The temperature, Lewis acid and chiralauxiliary may all be expected to influence the diastereoselectivity ofthe addition adduct. Finally, saponification under mild conditions (e.g.LiOH/H₂O at −10° C. to 30° C.) gives rise to the desired acid 5.

According, another aspect of this invention provides a method ofpreparing a compound of Formula I, comprising:

reacting a compound having the formula:

wherein R¹, R², R⁵ and R¹⁰ are as defined herein, with an amino acidhaving the formula:

wherein R⁶, R⁷, R^(a), R^(b), R^(c), R^(d), G, m, n and p are as definedherein.

The amino acids used in the synthesis of compounds of Formula I asillustrated in Schemes 1-4 and in the Examples are either commerciallyavailable or may be prepared according to the methods disclosed herein.For example, in certain embodiments the amino acids used to preparecompounds of Formula I include β-phenylglycine amino acids having theFormula 1A, γ-phenylglycine amino acids having the Formula 2A,β-phenylalanine amino acids having the Formula 3A, and γ-phenylalanineamino acids having the Formula 4A.

Methods of preparing amino acids of Formulas 1A-4A are shown in SchemesA-J.

Scheme A illustrates a method of preparing optionally substitutedβ-phenylglycine amino acids 25 and 26 of the Formula 1A wherein R⁸ is H,and R⁶, and R⁹ and are as defined herein, t is 0 to 4, and R⁷ is H or anamine protecting group. According to Scheme A, the acid 20 is convertedto an ester 21 wherein R′ is alkyl using standard conditions such astreatment with an appropriate alcohol (e.g. MeOH) in the presence of acatalytic amount of an acid such as concentrated H₂SO₄ or a couplingagent such as DCC/DMAP; or alternatively by treatment with anappropriate electrophile (e.g., MeI, EtBr, BnBr) in the presence of abase such as NEt₃/DMAP at an appropriate temperature (e.g., −20° C. to100° C.). The appropriate choice of ester is determined by theconditions required to reform the acid at the end of the synthesis, withmany appropriate examples and conditions being listed in ‘ProtectiveGroups in Organic Synthesis’ by Greene and Wuts, Wiley-Interscience,third edition, Chapter 5. Introduction of the hydroxymethyl group toprovide compound 22 may be performed by treatment with an appropriatealdehyde (e.g., formaldehyde) in the presence of base such as NaOEt atan appropriate temperature (e.g., −20° C. to room temperature).Activation of the alcohol group of compound 22 to form a leaving group(e.g., a mesylate, tosylate, halide) may be accomplished by treatmentwith, for example, methanesulphonyl chloride in the presence of excessbase such as NEt₃, DIPEA, or DBU at an appropriate temperature (e.g.,−20° C. to room temperature). In many cases the olefin 24 can beisolated directly from this procedure, in other cases warming (30° C. to100° C.) or additional base (e.g. DBU in the case of halide) may berequired to complete the elimination to provide compound 24. Theactivated olefin 24 may be treated with the desired primary amine (e.g.,ethylamine) in a suitable solvent, such as THF, at an appropriatetemperature (e.g., −20° C. to reflux) to generate the amino esterintermediate. In the case wherein compound 24 has an electron richaromatic ring or electron poor/bulky primary amine, heating (e.g.30-240° C. in a sealed tube) or microwave chemistry may be required.Protection of the amine group (for example as Boc-group) may beaccomplished using Boc₂O under standard conditions to provide compound23 wherein Pg is a protecting group. Alternative protecting groups maybe used, and many appropriate examples are listed in ‘Protective Groupsin Organic Synthesis’ by Greene and Wuts, Wiley-Interscience, thirdedition, Chapter 7. Saponification of the ester 23 to form the protectedamino acid 25 may be accomplished using conditions appropriate for theester (e.g., aqueous LiOH for methyl esters, hydrogenation for benzylesters, acid for t-butyl esters).

Alternatively, the activated olefin 24 may be treated with a secondaryamine (e.g., diethylamine) in a suitable solvent such as THF at anappropriate temperature (e.g., −20° C. to reflux) to generate theaminoester intermediate (not shown). In the case wherein compound 24 hasan electron rich aromatic ring or electron poor/bulky secondary amine,heating (e.g., 30-240° C. in a sealed tube) or microwave chemistry maybe required. Saponification of the ester to form the amino acid 26 maybe accomplished using conditions appropriate for the ester (e.g.,aqueous LiOH for methyl esters, hydrogenation for benzyl esters, acidfor t-butyl esters, etc.).

In an alternative to Scheme A, Pg may be substituted with R⁷ incompounds 23 and 25.

Scheme A1 shows an alternative to Scheme 1, wherein the activated olefin24 is reacted to form the amino acid 26A.

Scheme B shows a method of preparing optionally substitutedβ-phenylglycine amino acids 30 and 31 of Formula 1A wherein R⁸ is OH,and R⁶, and R⁹ are as defined herein, t is 0 to 4, and R⁷ is as definedherein or an amine protecting group. Oxidation of the unsaturated ester24 (prepared according to Scheme A), wherein t is 0-4 and R′ is alkyl,using a standard oxidizing agent such as MCPBA at an appropriatetemperature (room temperature to reflux) provides the epoxideintermediate 28. Intermediate 28 may be treated with an appropriateamine, typically at high temperature (e.g., 50-300° C.) and highpressure (e.g., in a sealed tube or a bomb) to give the amino alcohol 29or 30. If a secondary amine is used (such as in the preparation ofcompound 30), then deprotection of the ester using conditions listed in‘Protective Groups in Organic Synthesis’ by Greene and Wuts,Wiley-Interscience, third edition, Chapter 5 may be used (e.g., LiOH fora methyl ester, hydrogenation for a benzyl ester, etc). When a primaryamine is used (such as in the preparation of compound 29), protection ofthe amine (e.g., as a Boc-group using Boc anhydride) followed bydeprotection of the ester (using the above conditions) provide thehydroxylated amino acid 31.

Scheme C shows a method of preparing optionally substitutedβ-phenylglycine amino acids 36 of the Formula 1A wherein R⁸ is methyl,R⁶ is H, R⁷ is an amine protecting group t is 0 to 4, and R⁹ is asdefined herein. The ester 32, wherein R′″ is alkyl, can be treated witha base (e.g. NaOtBu) at an appropriate temperature (e.g., 0° C. toreflux) to form the anion, followed by addition of an electrophile(e.g., tert-butyl 2-bromoacetate) at an appropriate temperature (e.g.,−78° C. to room temperature) to give the homologated ester 33.Saponification of the t-butyl ester of compound 33 using an appropriateacid such as TFA or HCl at an appropriate temperature (e.g., 0° C. toreflux) provides compound 34. A Curtius rearrangement of compound 34using, for example, DPPA in the presence of mild base such as NEt₃ at anappropriate temperature (e.g., 0° C. to reflux), followed by treatmentof the reactive intermediate with an alcohol (e.g. t-BuOH), optionallyin the presence of a Lewis acid (e.g. SnCl₂) at higher temperature(e.g., 40-200° C.) provides compound 35 wherein Pg is an amineprotecting group. The choice of alcohol used to prepare compound 35determines the amine protecting group (e.g. t-BuOH provides theBoc-amine). Deprotection of the ester group of compound 35 usingstandard conditions (e.g., with LiOH when the protecting group is amethyl ester, hydrogenation for a benzyl ester, etc.) gives the acidcompound 36.

In one alternative of Scheme C, R⁸ may be methyl, H or F.

In another alternative of Scheme C, Pg may be substituted with R⁷ incompounds 35 and 36.

Scheme D shows a method of preparing optionally substitutedγ-phenylglycine amino acids 40 of Formula 2A wherein R^(c), R^(d), andR⁹ are as defined herein t is 0 to 4, R⁶ is H, and R⁷ is an amineprotecting group such as Boc. The starting unsaturated ester 24,prepared according to Scheme A, can be treated with a substitutednitromethane derivative (e.g. nitroethane) in the presence of a basesuch as DBU at an appropriate temperature (e.g., 0° C. to roomtemperature) to give the homologated adduct 37. The nitro group ofcompound 37 can be reduced using standard conditions (e.g.,hydrogenation, Zn/acid, etc.) at an appropriate temperature (e.g., roomtemperature to reflux), and the resulting intermediate can be cyclizedto give the lactam intermediate 38. Protection of the amine, for examplewith a Boc-group to provide compound 39, may be accomplished using Boc₂Ounder standard conditions. Alternative protecting groups may be used,and many appropriate examples are listed in ‘Protective Groups inOrganic Synthesis’ by Greene and Wuts, Wiley-Interscience, thirdedition, Chapter 7. Treatment of compound 39 with an aqueous base suchas LiOH or KOH at an appropriate temperature (e.g., 0 to 100° C.)effects ring opening of the lactam to give the appropriately substitutedprotected amino acid compound 40.

In one alternative of Scheme D, Boc may be replaced with R⁷ in compounds39 and 40.

Scheme D1 shows representative methods of forming the single enantiomersof the gamma amino acids 40d and 40e, wherein R^(c), R^(d), and R⁹ areas defined herein, t is 0 to 4, R⁶ is H, and R⁷ is an amine protectinggroup such as Boc. In one possible method, the racemic amino acid issubject to chiral chromatographic separation using a chiral stationaryphase. Alternatively, a diastereomeric mixture may be prepared whichcould be separated by conventional chromatographic techniques. Forexample, activation of compound 40 (e.g. COCl₂, base) and introductionof a chiral auxiliary (e.g. an Evans' oxazolidinone) in the presence ofa basic amine (e.g. Hunig's base) at −20° C. to 50° C. gives thediastereomeric mixture of compounds 40b and 40c. This mixture may beseparated using standard conditions (e.g. column chromatography, HPLC,SFC, etc.) to give the individual diastereomers. These may be convertedto the desired acids by cleavage of the chiral auxiliary (in the case ofan Evans' auxiliary, by using (for example) LiOH/HOOH at −15° C. to roomtemperature) to give the compounds 40d and 40e. The temperature may needto be kept low so as to prevent racemisation of the newly separatedchiral center.

Scheme E shows a method of making optionally substituted γ-phenylglycineamino acids 44 of Formula 2A wherein R⁸ is methyl, R⁶ is H, R⁷ is anamine protecting group, t is 0 to 4, and R⁹ is as defined herein. Theester 32, wherein R′″ is alkyl and t is 0-4, can be treated with asuitable base such as KOtBu at an appropriate temperature (e.g., 0° C.to reflux) to form the anion, followed by addition of an acrylate unit(e.g., t-butylacrylate) at a temperature ranging from −78° C. to roomtemperature to give the homologated ester 41. Saponification of thet-butyl ester of compound 41 by treatment with a suitable acid such asTFA or HCl at an appropriate temperature (e.g., 0° C. to reflux)provides compound 42. A Curtius rearrangement of compound 42 using, forexample, DPPA in the presence of mild base such as NEt₃ at anappropriate temperature (e.g., 0° C. to reflux), followed by treatmentof the reactive intermediate with an appropriate alcohol (e.g. tBuOH),optionally in the presence of a Lewis acid (e.g. SnCl₂) at elevatedtemperatures (e.g. 40-200° C.) provides compound 43. The choice ofalcohol determines the amine protecting group of compound 43 (e.g.,tBuOH provides the Boc-amine). Deprotection of the ester of compound 43under standard conditions (e.g., LiOH for a methyl ester, hydrogenationfor a benzyl ester, etc.) gives the acid 44.

In one alternative to Scheme E, Pg may be substituted with R⁷ incompounds 43 and 44.

Scheme F shows a method of preparing optionally substitutedβ-phenylalanine amino acids 48, 49 and 50 of Formula 3A wherein R⁶ is H,R⁷ is an amine protecting group, t is 0 to 4, and R⁹ is as definedherein. An appropriately substituted aldehyde 45 can be treated with acyanoacetate of the formula CN—CH₂CO₂R′″ wherein R′″ is alkyl (e.g.,ethyl 2-cyanoacetate) in the presence of a suitable base such aspiperidine at an appropriate temperature (e.g., room temperature toreflux) to give the unsaturated ester 46. Reduction of the olefin andthe nitrile groups of compound 46 to provide compound 47 may beaccomplished in a number of ways. For example, the olefin may be reducedwith any agent known to effect 1,4-reductions, such as NaBH₄. Thenitrile may be reduced using agents such as LiAlH₄ or NaBH₄ in thepresence of a Lewis acid such as BF₃OEt₂ or TFA. A number of alternativereducing agents may be used, such as those listed in ‘Reductions inOrganic Chemistry’ by Hudlicky, ACS monograph, 2^(nd) edition, Chapter18. If desired, the primary amine 47 can be monoalkylated orbisalkylated at this stage using standard conditions (e.g., reductiveamination using an appropriate aldehyde, Lewis acid and reducing agent)to provide intermediates (not shown) en route to compounds 48 and 49. Toprepare primary and secondary amines, protection may be accomplishedusing any number of protecting groups (e.g. ‘Protective Groups inOrganic Synthesis’ by Greene and Wuts, Wiley-Interscience, thirdedition, Chapter 7), for example as a Boc-group using Boc anhydride at0° C. to room temperature. Cleavage of the ester group to form the aminoacid 48, 49 or 50 may be accomplished using an aqueous bases such asLiOH or KOH, or any of the alternative reagents listed in theaforementioned ‘Protecting Groups’ text (e.g., hydrogenation for abenzyl ester).

In one alternative to Scheme F, Pg may be substituted with R⁷ incompounds 49 or 50.

Scheme G shows a method of preparing optionally substitutedα-phenylalanine amino acids 54 of Formula 4A, wherein R⁶ is H, R⁷ is anamine protecting group, t is 0 to 4, and R⁹ is as defined herein. Anappropriately substituted acid 51 may be reduced to the benzyl alcohol52 using for example LiAlH₄ at a temperature ranging from roomtemperature to reflux. The alcohol group of compound 52 can be activatedas a leaving group (e.g. halide, mesylate, etc.) using, for example,PBr₃, MsCl/NEt₃, etc. Displacement of this leaving group using aprotected glycine derivative such as ethyl2-(diphenylmethyleneamino)acetate in the presence of strong base such asLDA, nBuLi provides the amino ester intermediate 53 wherein R¹ is alkyland Pg is a protecting group. Appropriate protecting groups are listedin ‘Protective Groups in Organic Synthesis’ by Greene and Wuts,Wiley-Interscience). The amine protecting group may be changed at thisstage, for example to introduce a Boc-group. Subsequent deprotection ofthe ester 53 (e.g., using 3N HCl, LiOH, hydrogenation for a benzylester, etc.) at an appropriate temperature (e.g., 0° C. to reflux)provides the desired N-protected amino acid 54.

In one alternative to Scheme G, Pg may be substituted with R⁷ incompound 54 after the deprotection of compound 53.

Scheme H shows a method of preparing optionally substitutedγ-phenylglycine amino acids 56 of Formula 2A wherein R⁶ and R⁸ togetherwith the atoms to which they are attached form a spirocyclicheterocyclic ring, R⁷ is an amine protecting group, t is 0 to 4, and R⁹is as defined herein. According to Scheme H, the unsaturated ester 24can be treated with a suitably protected glycine derivative (e.g.,benzylglycine) and formaldehyde under dry conditions (e.g., withaddition of molecular sieves) at an appropriate temperature (e.g., roomtemperature to reflux) to generate compound 55. Cleavage of the benzylgroup using standard conditions (e.g., via hydrogenation,1-chloroethylformate, etc.) followed by addition of an amine protectinggroup such as a Boc-group and cleavage of the ester under standardconditions (e.g. LiOH for a methyl ester, acid for a t-butyl ester,etc., at 0° C. to reflux) provides the N-protected amino acid 56.

In one alternative to Scheme H, Pg may be substituted with R⁷ incompound 56.

Scheme I shows a method of preparing optionally substitutedβ-phenylalanine amino acids 61 and 62 of Formula 3A wherein R⁶ and R^(b)together with the atoms to which they are attached form a heterocyclicring, and R⁷ and R⁹ are as defined herein and t is 0 to 4. The acid 57is converted to an ester 58 using standard conditions such as treatmentwith an appropriate alcohol (e.g., MeOH) in the presence of eithercatalytic acid (e.g. concentrated H₂SO₄ or TMSCl) or a coupling agent(e.g. DCC/DMAP); or alternatively by treatment with an appropriateelectrophile (e.g. MeI, EtBr, BnBr) in the presence of a suitable basesuch as NEt₃/DMAP at appropriate temperatures (e.g., −20° C. to 100°C.). The appropriate choice of ester is determined by the conditionsrequired to reform the acid at the end of the synthesis, such asdescribed in ‘Protective Groups in Organic Synthesis’ by Greene andWuts, Wiley-Interscience, third edition, Chapter 5. Cyclization ofcompound 58 to provide compound 59 may be achieved using, for example,N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine in thepresence of TFA. This particular set of reagents generates thebenzylamine, which can be cleaved to provide compound 60 under standardconditions such as such as hydrogenation at −20° C. to 50° C. or anyother standard conditions such as those listed in ‘Protective Groups inOrganic Synthesis’ by Greene and Wuts, Wiley-Interscience, thirdedition, Chapter 7. Protection of the free amine of compound 60 with analternative protecting group (e.g., Boc) using reagents listed in theaforementioned text, such as Boc-anhydride, followed by cleavage of theester using standard conditions appropriate for the ester (e.g. aqueousLiOH for methyl esters, hydrogenation for benzyl esters, acid fort-butyl esters) provides the acid compound 61. Alternatively, the freeamine can be functionalized further (e.g. using alkylation, reductiveamination, or acylation conditions), followed by ester cleavage togenerate the tertiary amino acid compound 62.

Either enantiomer of the b-amino acids may be prepared using a proceduresuch as that shown in Scheme J. A 2-phenylacetate coupled with anappropriate chiral auxiliary (R*) (for example, an Evans' auxiliary or aSultam) with the appropriate stereochemistry to generate the desiredchemistry at the b-position of the amino acid may be treated with animine or iminium ion synthon (e.g. prepared in situ by the presence of aLewis acid (eg. TiCl₄) and an appropriately substitutedalkoxymethanamine or N-(alkoxymethyl)amide/carbamate at −100° C. to 50°C.). The asymmetric addition may require the presence of Lewis acids(eg. TiCl₄), amine bases (eg. Hunig's base) and lower temperatures (e.g.−100° C. to 0° C.) to generate the best levels of stereochemicalinduction. If the de is lower than required, the separate diastereomersmay be separated at this stage by (for example) chromatography orcrystallization. Cleavage of the chiral auxiliary, using methods knownto cleave the chosen auxiliary (e.g. LiOH/H₂O₂ at −50° C. to 50° C. forthe Evans auxiliary) then leads to the desired N-protected b-amino acidwith the desired stereochemistry at the b-position. Additionally, if R⁶is also a protecting group (e.g. 2,4-dimethoxybenzyl), it may be removedin the presence of the Boc-group (e.g. hydrogenation or DDQ, etc.) togive the Boc-amino acid, which upon removal of the Boc-group wouldprovide the primary amine, which may be further functionalized byalkylation, acylation or reductive amination (either prior to or aftercoupling with the pyrimidine-piperazine unit).

In preparing compounds of Formula I, protection of remotefunctionalities (e.g., primary or secondary amines, etc.) ofintermediates may be necessary. The need for such protection will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. Suitable amino-protecting groups (NH-Pg)include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Theneed for such protection is readily determined by one skilled in theart. For a general description of protecting groups and their use, seeT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

Methods of Separation

In any of the synthetic methods for preparing compounds of Formula I, itmay be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified to the desired degree ofhomogeneity by the techniques common in the art. Typically suchseparations involve multiphase extraction, crystallization from asolvent or solvent mixture, distillation, sublimation, orchromatography. Chromatography can involve any number of methodsincluding, for example: reverse-phase and normal phase; size exclusion;ion exchange; high, medium and low pressure liquid chromatographymethods and apparatus; small scale analytical; simulated moving bed(SMB) and preparative thin or thick layer chromatography, as well astechniques of small scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a reactionmixture with a reagent selected to bind to or render otherwise separablea desired product, unreacted starting material, reaction by product, orthe like. Such reagents include adsorbents or absorbents such asactivated carbon, molecular sieves, ion exchange media, or the like.Alternatively, the reagents can be acids in the case of a basicmaterial, bases in the case of an acidic material, binding reagents suchas antibodies, binding proteins, selective chelators such as crownethers, liquid/liquid ion extraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,J. Chromatogr., (1975) 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine(amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−)menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem.,(1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111). By method (3), a racemic mixture of two enantiomers canbe separated by chromatography using a chiral stationary phase (“ChiralLiquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, NewYork; Okamoto, J. of Chromatogr., (1990) 513:375-378). Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

Methods of Treatment with Compounds of Formula I

The compounds of the present invention can be used as prophylactics ortherapeutic agents for treating diseases or disorders mediated bymodulation or regulation of AKT protein kinases, tyrosine kinases,additional serine/threonine kinases, and/or dual specificity kinases.AKT protein kinase mediated conditions that can be treated according tothe methods of this invention include, but are not limited to,inflammatory, hyperproliferative cardiovascular, neurodegenerative,gynecological, and dermatological diseases and disorders.

In one embodiment, said pharmaceutical composition is for the treatmentof hyperproliferative disorders, including cancers of the followingcategories: (1) Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; (2) Lung: bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small celllung, small cell lung; (3) Gastrointestinal: esophagus (squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach(carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma,insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), smallbowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); (4) Genitourinary tract: kidney (adenocarcinoma, Wilm'stumor [nephroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); (5) Liver: hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, hemangioma; (6) Bone: osteogenic sarcoma (osteosarcoma),fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'ssarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma,malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginousexostoses), benign chondroma, chondroblastoma, chondromyxofibroma,osteoid osteoma and giant cell tumors; (7) Nervous system: skull(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastomamultiform. oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); (8)Gynecological: uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma[serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); (9)Hematologic: blood (myeloid leukemia [acute and chronic], acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma [malignant lymphoma]; (10) Skin:advanced melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma,angioma, dermatofibroma, keloids, psoriasis; (11) Adrenal glands:neuroblastoma; (12) Breast: metastatic breast; breast adenocarcinoma;(13) Colon; (14) Oral cavity; (15) Hairy cell leukemia; (16) Head andneck; (17) and others including refractory metastatic disease; Kaposi'ssarcoma; Bannayan-Zonana syndrome; and Cowden disease orLhermitte-Duclos disease, among other kinds of hyperproliferativedisorders.

Compounds and methods of this invention can be also used to treatdiseases and conditions such as rheumatoid arthritis, osteoarthritis,Chron's disease, angiofibroma, ocular diseases (e.g., retinalvascularisation, diabetic retinopathy, age-related macular degeneration,macular degeneration, etc.), multiple sclerosis, obesity, Alzheimer'sdisease, restenosis, autoimmune diseases, allergy, asthma,endometriosis, atherosclerosis, vein graft stenosis, peri-anastomaticprothetic graft stenosis, prostate hyperplasia, chronic obstructivepulmonary disease, psoriasis, inhibition of neurological damage due totissue repair, scar tissue formation (and can aid in wound healing),multiple sclerosis, inflammatory bowel disease, infections, particularlybacterial, viral, retroviral or parasitic infections (by increasingapoptosis), pulmonary disease, neoplasm, Parkinson's disease, transplantrejection (as an immunosupressant), septic shock, etc.

Accordingly, another aspect of this invention provides a method oftreating diseases or medical conditions in a mammal mediated by AKTprotein kinases, comprising administering to said mammal one or morecompounds of Formula I or a pharmaceutically acceptable salt or prodrugthereof in an amount effective to treat or prevent said disorder.

The phrase “effective amount” means an amount of compound that, whenadministered to a mammal in need of such treatment, is sufficient to (i)treat or prevent a particular disease, condition, or disorder mediatedby the activity of one or more AKT protein kinases, tyrosine kinases,additional serine/threonine kinases, and/or dual specificity kinases,(ii) attenuate, ameliorate, or eliminate one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevent or delaythe onset of one or more symptoms of the particular disease, condition,or disorder described herein. In the case of cancer, an effective amountof the drug may reduce the number of cancer cells; reduce the tumorsize; inhibit (i.e., slow to some extent and preferably stop) cancercell infiltration into peripheral organs; inhibit (i.e., slow to someextent and preferably stop) tumor metastasis; inhibit, to some extent,tumor growth; and/or relieve to some extent one or more of the symptomsassociated with the cancer. To the extent the drug may prevent growthand/or kill existing cancer cells, it may be cytostatic and/orcytotoxic. For cancer therapy, efficacy can be measured, for example, byassessing the time to disease progression (TTP) and/or determining theresponse rate (RR).

The amount of a compound of Formula I that will correspond to such anamount will vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of themammal in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art.

“Treating” is intended to mean at least the mitigation of a diseasecondition in a mammal, such as a human, that is affected, at least inpart, by the activity of one or more AKT protein kinases, tyrosinekinases, additional serine/threonine kinases, and/or dual specificitykinases. The terms “treat” and “treatment” refer to both therapeutictreatment and prophylactic or preventative measures, wherein the objectis to prevent or slow down (lessen) an undesired physiological change ordisorder. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. Those in need of treatment include those already with thecondition or disorder as well as those found to be predisposed to havingthe disease condition but have not yet been diagnosed as having it;modulating and/or inhibiting the disease condition. The terms“treating”, “treat”, or “treatment” embrace both preventative, i.e.,prophylactic, and palliative treatment.

As used herein, the term “mammal” refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

This invention also provides compounds of Formula I for use in thetreatment of AKT protein kinase-mediated conditions.

An additional aspect of the invention is the use of a compound ofFormula I in the preparation of a medicament for therapy, such as forthe treatment or prevention of AKT protein kinase-mediated conditions.

Combination Therapy

The compounds of the present invention can be used in combination withone or more additional drugs such as described below. The dose of thesecond drug can be appropriately selected based on a clinically employeddose. The proportion of the compound of the present invention and thesecond drug can be appropriately determined according to theadministration subject, the administration route, the target disease,the clinical condition, the combination, and other factors. In caseswhere the administration subject is a human, for instance, the seconddrug may be used in an amount of 0.01 to 100 parts by weight per part byweight of the compound of the present invention.

The second compound of the pharmaceutical combination formulation ordosing regimen preferably has complementary activities to the compoundof this invention such that they do not adversely affect each other.Such drugs are suitably present in combination in amounts that areeffective for the purpose intended. Accordingly, another aspect of thepresent invention provides a composition comprising a compound of thisinvention in combination with a second drug, such as described herein.

A compound of this invention and the additional pharmaceutically activedrug(s) may be administered together in a unitary pharmaceuticalcomposition or separately and, when administered separately this mayoccur simultaneously or sequentially in any order. Such sequentialadministration may be close in time or remote in time. The amounts ofthe compound of this invention and the second drug(s) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect.

The combination therapy may provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect may be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e., serially, whereas incombination therapy, effective dosages of two or more active ingredientsare administered together.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer, regardless of mechanism of action. Chemotherapeuticagents include compounds used in “targeted therapy” and conventionalchemotherapy.

Examples of chemotherapeutic agents include Erlotinib (TARCEVA®,Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.),Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer),Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis),PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU(5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth),Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH66336), Sorafenib (BAY43-9006, Bayer Labs), Irinotecan (CAMPTOSAR®,Pfizer) and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271;Sugen), alkylating agents such as thiotepa and CYTOXAN®cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gamma1I and calicheamicinomegaI1 (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin,including dynemicin A; bisphosphonates, such as clodronate; anesperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL®(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France);chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin;vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine;NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate;daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11;topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO);retinoids such as retinoic acid; and pharmaceutically acceptable salts,acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifinecitrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase,which regulates estrogen production in the adrenal glands, such as, forexample, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrolacetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole,RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide,nilutamide, bicalutamide, leuprolide, and goserelin; as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors; (v) lipid kinase inhibitors; (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, suchas, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; a topoisomerase 1 inhibitorsuch as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptablesalts, acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” aretherapeutic antibodies such as alemtuzumab (Campath), bevacizumab(AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab(VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec),pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®,Genentech), tositumomab (Bexxar, Corixia), and the antibody drugconjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

Humanized monoclonal antibodies with therapeutic potential aschemotherapeutic agents in combination with the PI3K inhibitors of theinvention include: alemtuzumab, apolizumab, aselizumab, atlizumab,bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumabmertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab,daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab,fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab,labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab,motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab,ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab,pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab,reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab,sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan,tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab,trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab,urtoxazumab, and visilizumab.

Routes of Administration

The compounds of the invention may be administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, parenteral (including subcutaneous, intramuscular, intravenous,intraarterial, intradermal, intrathecal and epidural), transdermal,rectal, nasal, topical (including buccal and sublingual), vaginal,intraperitoneal, intrapulmonary and intranasal. It will be appreciatedthat the preferred route may vary with for example the condition of therecipient. Where the compound is administered orally, it may beformulated as a pill, capsule, tablet, etc. with a pharmaceuticallyacceptable carrier or excipient. Where the compound is administeredparenterally, it may be formulated with a pharmaceutically acceptableparenteral vehicle and in a unit dosage injectable form, as detailedbelow.

Pharmaceutical Formulations

In order to use a compound of this invention for the therapeutictreatment (including prophylactic treatment) of mammals includinghumans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. According tothis aspect of the invention there is provided a pharmaceuticalcomposition that comprises a compound of this invention. In certainembodiments, the pharmaceutical composition comprises a compound ofFormula I in association with a pharmaceutically acceptable diluent orcarrier.

The pharmaceutical compositions of the invention are formulated, dosedand administered in a fashion, i.e., amounts, concentrations, schedules,course, vehicles and route of administration, consistent with goodmedical practice. Factors for consideration in this context include theparticular disorder being treated, the particular mammal being treated,the clinical condition of the individual patient, the cause of thedisorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. The therapeutically effective amount ofthe compound to be administered will be governed by such considerations,and is the minimum amount necessary to prevent, ameliorate, or treat thedisorder. The compound of the present invention is typically formulatedinto pharmaceutical dosage forms to provide an easily controllabledosage of the drug and to enable patient compliance with the prescribedregimen.

The composition for use herein is preferably sterile. In particular,formulations to be used for in vivo administration must be sterile. Suchsterilization is readily accomplished, for example, by filtrationthrough sterile filtration membranes. The compound ordinarily can bestored as a solid composition, a lyophilized formulation or as anaqueous solution.

Pharmaceutical formulations of the compounds of the present inventionmay be prepared for various routes and types of administration. Forexample, a compound of this invention having the desired degree ofpurity may optionally be mixed with pharmaceutically acceptablediluents, carriers, excipients or stabilizers (Remington'sPharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), in the formof a lyophilized formulation, a milled powder, or an aqueous solution.Formulation may be conducted by mixing at ambient temperature at theappropriate pH, and at the desired degree of purity, withphysiologically acceptable carriers, i.e., carriers that are non-toxicto recipients at the dosages and concentrations employed. The pH of theformulation depends mainly on the particular use and the concentrationof compound, but may range from about 3 to about 8. Formulation in anacetate buffer at pH 5 is a suitable embodiment. The formulations may beprepared using conventional dissolution and mixing procedures. Forexample, the bulk drug substance (i.e., compound of the presentinvention or stabilized form of the compound (e.g., complex with acyclodextrin derivative or other known complexation agent) is dissolvedin a suitable solvent in the presence of one or more excipients.

The particular carrier, diluent or excipient used will depend upon themeans and purpose for which the compound of the present invention isbeing applied. Solvents are generally selected based on solventsrecognized by persons skilled in the art as safe (GRAS) to beadministered to a mammal. In general, safe solvents are non-toxicaqueous solvents such as water and other non-toxic solvents that aresoluble or miscible in water. Suitable aqueous solvents include water,ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG300), etc. and mixtures thereof. Acceptable diluents, carriers,excipients and stabilizers are nontoxic to recipients at the dosages andconcentrations employed, and include buffers such as phosphate, citrateand other organic acids; antioxidants including ascorbic acid andmethionine; preservatives (such as octadecyldimethylbenzyl ammoniumchloride; hexamethonium chloride; benzalkonium chloride, benzethoniumchloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methylor propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; andm-cresol); low molecular weight (less than about 10 residues)polypeptides; proteins, such as serum albumin, gelatin, orimmunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone;amino acids such as glycine, glutamine, asparagine, histidine, arginine,or lysine; monosaccharides, disaccharides and other carbohydratesincluding glucose, mannose, or dextrins; chelating agents such as EDTA;sugars such as sucrose, mannitol, trehalose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (e.g., Zn-proteincomplexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ orpolyethylene glycol (PEG). The formulations may also include one or morestabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents and other known additives to provide an elegantpresentation of the drug (i.e., a compound of the present invention orpharmaceutical composition thereof) or aid in the manufacturing of thepharmaceutical product (i.e., medicament). The active pharmaceuticalingredients may also be entrapped in microcapsules prepared, forexample, by coacervation techniques or by interfacial polymerization,for example, hydroxymethylcellulose or gelatin-microcapsules andpoly-(methylmethacrylate) microcapsules, respectively, in colloidal drugdelivery systems (for example, liposomes, albumin microspheres,microemulsions, nanoparticles and nanocapsules) or in macroemulsions.Such techniques are disclosed in Remington's Pharmaceutical Sciences16th edition, Osol, A. Ed. (1980). A “liposome” is a small vesiclecomposed of various types of lipids, phospholipids and/or surfactantwhich is useful for delivery of a drug (such as a compound of Formula Iand, optionally, an additional therapeutic agent) to a mammal. Thecomponents of the liposome are commonly arranged in a bilayer formation,similar to the lipid arrangement of biological membranes.

Sustained-release preparations of compounds of this invention may beprepared. Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I, which matrices are in the form of shapedarticles, e.g., films, or microcapsules. Examples of sustained-releasematrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.

The pharmaceutical compositions of compounds of this invention may be inthe form of a sterile injectable preparation, such as a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, such as a solution in 1,3-butanediol or prepared as alyophilized powder. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile fixed oils may conventionally be employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid may likewise be used in the preparationof injectables.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The compositions of the invention may also be in a form suitable fororal use (for example as tablets, lozenges, hard or soft capsules,aqueous or oily suspensions, emulsions, dispersible powders or granules,syrups or elixirs), for topical use (for example as creams, ointments,gels, or aqueous or oily solutions or suspensions), for administrationby inhalation (for example as a finely divided powder or a liquidaerosol), for administration by insufflation (for example as a finelydivided powder)

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),coloring agents, flavoring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, esters or partial esters derived from fatty acids and hexitolanhydrides (for example sorbitan monooleate) and condensation productsof the said partial esters with ethylene oxide such as polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening,flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient that is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols. Formulations suitablefor vaginal administration may be presented as pessaries, tampons,creams, gels, pastes, foams or spray formulations containing in additionto the active ingredient such carriers as are known in the art to beappropriate.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for transdermal administration may be in the form of thosetransdermal skin patches that are well known to those of ordinary skillin the art.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis disorders as described below.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. For example, an article for distribution caninclude a container having deposited therein the pharmaceuticalformulation in an appropriate form. Suitable containers are well knownto those skilled in the art and include materials such as bottles(plastic and glass), sachets, ampoules, plastic bags, metal cylinders,and the like. The container may also include a tamper-proof assemblageto prevent indiscreet access to the contents of the package. Inaddition, the container has deposited thereon a label that describes thecontents of the container. The label may also include appropriatewarnings. The formulations may also be packaged in unit-dose ormulti-dose containers, for example sealed ampoules and vials, and may bestored in a freeze-dried (lyophilized) condition requiring only theaddition of the sterile liquid carrier, for example water, for injectionimmediately prior to use. Extemporaneous injection solutions andsuspensions are prepared from sterile powders, granules and tablets ofthe kind previously described. Preferred unit dosage formulations arethose containing a daily dose or unit daily sub-dose, as herein aboverecited, or an appropriate fraction thereof, of the active ingredient.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefore. Veterinary carriers are materials useful for thepurpose of administering the composition and may be solid, liquid orgaseous materials which are otherwise inert or acceptable in theveterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered parenterally, orally or byany other desired route.

The amount of a compound of this invention that is combined with one ormore excipients to produce a single dosage form will necessarily varydepending upon the subject treated, the severity of the disorder orcondition, the rate of administration, the disposition of the compoundand the discretion of the prescribing physician. In one embodiment, asuitable amount of a compound of this invention is administered to amammal in need thereof. Administration in one embodiment occurs in anamount between about 0.001 mg/kg of body weight to about 60 mg/kg ofbody weight per day. In another embodiment, administration occurs in anamount between 0.5 mg/kg of body weight to about 40 mg/kg of body weightper day. In some instances, dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smalldoses for administration throughout the day. For further information onroutes of administration and dosage regimes, see Chapter 25.3 in Volume5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman ofEditorial Board), Pergamon Press 1990, which is specificallyincorporated herein by reference.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the disordersdescribed above is provided. In one embodiment, the kit comprises acontainer comprising a compound of this invention. Suitable containersinclude, for example, bottles, vials, syringes, blister pack, etc. Thecontainer may be formed from a variety of materials such as glass orplastic. The container may hold a compound of this invention or aformulation thereof which is effective for treating the condition andmay have a sterile access port (for example, the container may be anintravenous solution bag or a vial having a stopper pierceable by ahypodermic injection needle).

The kit may further comprise a label or package insert on or associatedwith the container. The term “package insert” is used to refer toinstructions customarily included in commercial packages of therapeuticproducts, that contain information about the indications, usage, dosage,administration, contraindications and/or warnings concerning the use ofsuch therapeutic products. In one embodiment, the label or packageinserts indicates that the composition comprising a compound of thisinvention can be used to treat a disorder mediated, for example, by AKTkinase. The label or package insert may also indicate that thecomposition can be used to treat other disorders.

In certain embodiments, the kits are suitable for the delivery of solidoral forms of a compound of this invention, such as tablets or capsules.Such a kit preferably includes a number of unit dosages. Such kits caninclude a card having the dosages oriented in the order of theirintended use. An example of such a kit is a “blister pack”. Blisterpacks are well known in the packaging industry and are widely used forpackaging pharmaceutical unit dosage forms. If desired, a memory aid canbe provided, for example in the form of numbers, letters, or othermarkings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

According to another embodiment, a kit may comprise (a) a firstcontainer with a compound of this invention contained therein; and (b) asecond container with a second pharmaceutical formulation containedtherein, wherein the second pharmaceutical formulation comprises asecond compound useful for treating a disorder mediated by AKT kinase.Alternatively, or additionally, the kit may further comprise a thirdcontainer comprising a pharmaceutically-acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

The kit may further comprise directions for the administration of thecompound of this invention and, if present, the second pharmaceuticalformulation. For example, if the kit comprises a first compositioncomprising a compound of this invention and a second pharmaceuticalformulation, the kit may further comprise directions for thesimultaneous, sequential or separate administration of the first andsecond pharmaceutical compositions to a patient in need thereof.

In certain other embodiments wherein the kit comprises a composition ofthis invention and a second therapeutic agent, the kit may comprise acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. In certainembodiments, the kit comprises directions for the administration of theseparate components. The kit form is particularly advantageous when theseparate components are preferably administered in different dosageforms (e.g., oral and parenteral), are administered at different dosageintervals, or when titration of the individual components of thecombination is desired by the prescribing physician.

Accordingly, a further aspect of this invention provides a kit fortreating a disorder or disease mediated by Akt kinase, wherein said kitcomprises a) a first pharmaceutical composition comprising a compound ofthis invention or a pharmaceutically acceptable salt thereof; and b)instructions for use.

In certain embodiments, the kit further comprises (c) a secondpharmaceutical composition, wherein the second pharmaceuticalcomposition comprises a second compound suitable for treating a disorderor disease mediated by Akt kinase. In certain embodiment comprising asecond pharmaceutical composition, the kit further comprisesinstructions for the simultaneous, sequential or separate administrationof said first and second pharmaceutical compositions to a patient inneed thereof. In certain embodiments, said first and secondpharmaceutical compositions are contained in separate containers. Inother embodiments, said first and second pharmaceutical compositions arecontained in the same container.

Although the compounds of Formula I are primarily of value astherapeutic agents for use in mammals, they are also useful whenever itis required to control AKT protein kinases, tyrosine kinases, additionalserine/threonine kinases, and/or dual specificity kinases. Thus, theyare useful as pharmacological standards for use in the development ofnew biological tests and in the search for new pharmacological agents.

The activity of the compounds of this invention may be assayed for AKTprotein kinases, tyrosine kinases, additional serine/threonine kinases,and/or dual specificity kinases in vitro, in vivo, or in a cell line. Invitro assays include assays that determine inhibition of the kinaseactivity. Alternate in vitro assays quantitate the ability of theinhibitor to bind to kinases and may be measured either byradiolabelling the inhibitor prior to binding, isolating theinhibitor/kinase complex and determining the amount of radiolabel bound,or by running a competition experiment where new inhibitors areincubated with known radioligands. These and other useful in vitro andcell culture assays are well known to those of skill in the art.

Although the invention has been described and illustrated with a certaindegree of particularity, it is understood that the present disclosurehas been made only by way of example, and that numerous changes in thecombination and arrangement of parts can be resorted to by those skilledin the art without departing from the spirit and scope of the invention,as hereinafter claimed.

BIOLOGICAL EXAMPLES AKT-1 Kinase Assay

The activity of the compounds described in the present invention may bedetermined by the following kinase assay, which measures thephosphorylation of a fluorescently-labeled peptide by full-length humanrecombinant active AKT-1 by fluorescent polarization using acommercially available IMAP kit.

The assay materials are obtained from an IMAP AKT Assay Bulk Kit,product #R8059, from Molecular Devices, Sunnyvale, Calif. The kitmaterials include an IMAP Reaction Buffer (5×). The diluted 1×IMAPReaction Buffer contained 10 mM Tris-HCl, pH 7.2, 10 mM MgCl₂, 0.1% BSA,0.05% NaN₃. DTT is routinely added to a final concentration of 1 mMimmediately prior to use. Also included is IMAP Binding Buffer (5×), andIMAP Binding Reagent. The Binding Solution is prepared as a 1:400dilution of IMAP Binding Reagent into 1×IMAP Binding Buffer.

The fluorescein-labeled AKT Substrate (Crosstide) has the sequence(Fl)-GRPRTSSFAEG. A stock solution of 20 μM is made up in 1×IMAPReaction Buffer.

The plates used include a Costar 3657 (382-well made of polypropyleneand having a white, v-bottom) that is used for compound dilution and forpreparing the compound-ATP mixture. The assay plate is a PackardProxyPlate™-384 F.

The AKT-1 used is made from full-length, human recombinant AKT-1 that isactivated with PDK1 and MAP kinase 2.

To perform the assay, stock solutions of compounds at 10 mM in DMSO areprepared. The stock solutions and the control compound are seriallydiluted 1:2 nine times into DMSO (10 μL of compound+10 μL of DMSO) togive 50× dilution series over the desired dosing range. Next, 2.1-μLaliquots of the compounds in DMSO are transferred to a Costar 3657 platecontaining 50 μL of 10.4 μM ATP in 1×IMAP Reaction Buffer containing 1mM DTT. After thorough mixing, 2.5-μL aliquots are transferred to aProxyPlate™-384 F plate.

The assay is initiated by the addition of 2.5-μL aliquots of a solutioncontaining 200 nM of fluorescently-labeled peptide substrate and 4 nMAKT-1. The plate is centrifuged for 1 minute at 1000 g and incubated for60 minute at ambient temperature. The reaction is then quenched by theaddition of 15 μL of Binding Solution, centrifuged again and incubatedfor an additional 30 minutes at ambient temperature prior to reading ona Victor 1420 Multilabel HTS Counter configured to measure fluorescencepolarization.

The compounds of Examples 1-324 were tested in the above assay and foundto have an IC₅₀ of less than <10 μM.

PREPARATIVE EXAMPLES

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other compounds of Formula I, and alternative methods for preparingthe compounds of this invention are deemed to be within the scope ofthis invention. For example, the synthesis of non-exemplified compoundsaccording to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge, and were used without further purification unlessotherwise indicated. Tetrahydrofuran (THF), dichloromethane (DCM),toluene, and dioxane were purchased from Aldrich in Sure seal bottlesand used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

¹H NMR spectra were recorded on a Varian instrument operating at 400MHz. ¹H-NMR spectra were obtained as CDCl₃, CD₃OD, D₂O or d₆-DMSOsolutions (reported in ppm), using tetramethylsilane (0.00 ppm) orresidual solvent (CDCl₃: 7.25 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79 ppm;d₆-DMSO: 2.50 ppm) as the reference standard. When peak multiplicitiesare reported, the following abbreviations are used: s (singlet), d(doublet), t (triplet), m (multiplet), br (broadened), dd (doublet ofdoublets), dt (doublet of triplets). Coupling constants, when given, arereported in Hertz (Hz).

Example 1

Preparation of2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onedihydrochloride

Step 1:

To a 1 L round-bottom flask were added (R)-(+)-Pulegone (76.12 g, 0.5mmol), anhydrous NaHCO₃ (12.5 g) and anhydrous ether (500 mL). Thereaction mixture was cooled with ice-bath under nitrogen. The bromine(25.62 mL, 0.5 mmol) was added dropwise over 30 minutes. The mixture wasfiltered and carefully added to NaOEt (21%, 412 mL, 1.11 mmol) in anice-cooled bath. The mixture was stirred at room temperature overnightand then 1 L of 5% HCl and 300 mL of ether were added. The aqueous phasewas extracted with ether (2×300 mL). The combined organic phase waswashed with water, dried and concentrated. The residue was added to awarmed solution of semicarbazide hydrochloride (37.5 g) and NaOAc (37.5g) in water (300 mL), and then boiling ethanol (300 mL) was added togive a clear solution. The mixture was refluxed for 2.5 hours and thenstirred at room temperature overnight. The mixture was treated with 1 Lof water and 300 mL of ether. The aqueous phase was extracted with ether(2×300 mL). The combined organic phase was washed with water, dried andconcentrated. The residue was purified by vacuum distillation (73-76° C.at 0.8 mm Hg) to give (2R)-ethyl2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (63 g, 64%). ¹H NMR(CDCl₃, 400 MHz) δ 4.13 (m, 2H), 3.38 (d, J=16 Hz, 0.5H), 2.93 (m,0.5H), 2.50-2.17 (m, 2H), 1.98 (m, 1H), 1.76 (m, 1H), 1.23 (m, 6H), 1.05(m, 6H).

Step 2:

(2R)-Ethyl 2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (24 g,0.122 mol) in ethyl acetate (100 mL) was cooled to −68° C. with dryice/isopropanol. Ozonized oxygen (5-7 ft³ h⁻¹ of O₂) was bubbled throughthe solution for 3.5 hours. The reaction mixture was flushed withnitrogen at room temperature until the color disappeared. The ethylacetate was removed under vacuum and the residue was dissolved in 150 mLof acetic acid and cooled by ice water. Then 45 g of zinc powder wereadded. The solution was stirred for 30 minutes and then filtered. Thefiltrate was neutralized with 2N NaOH (1.3 L) and NaHCO₃. The aqueousphase was extracted with ether (3×200 mL). The organic phase wascombined, washed with water, dried and concentrated to afford (2R)-ethyl2-methyl-5-oxocyclopentanecarboxylate (20 g, 96%). ¹H NMR (CDCl₃, 400MHz) δ 4.21 (m, 2H), 2.77 (d, J=11.2 Hz, 1H), 2.60 (m, 1H), 2.50-2.10(m, 3H), 1.42 (m, 1H), 1.33 (m, 3H), 1.23 (m, 3H).

Step 3:

To a solution of a mixture of (2R)-ethyl2-methyl-5-oxocyclopentanecarboxylate (20 g, 117.5 mmol) and thiourea(9.2 g, 120.9 mmol) in ethanol (100 mL) was added KOH (8.3 g, 147.9mmol) in water (60 mL). The mixture was refluxed for 10 hours. Aftercooling, the solvent was removed and the residue was neutralized withconcentrated HCl (12 mL) at 0° C. and then extracted with DCM (3×150mL). The solvent was removed and the residue was purified by silica gelchromatography, eluting with Hexane/ethyl acetate (2:1) to give(R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12g, 56%). MS (APCI+) [M+H] ⁺183.

Step 4:

To a suspension of(R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12g, 65.8 mmol) in distilled water (100 mL) was added Raney Nickel (15 g)and NH₄OH (20 mL). The mixture was refluxed for 3 hours then filtered,and the filtrate was concentrated to afford(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.89 g, 99%).MS (APCI+) [M+H] ⁺151.

Step 5:

A mixture of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol(5.8 g, 38.62 mmol) in POCl₃ (20 mL) was refluxed for 5 minutes. ExcessPOCl₃ was removed under vacuum and the residue was dissolved in DCM (50mL). The mixture was then added to saturated NaHCO₃ (200 mL). Theaqueous phase was extracted with DCM (3×100 mL), and the combinedorganic phases were dried and concentrated. The residue was purified bysilica gel chromatography, eluting with ethyl acetate to give(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (3.18 g,49%). ¹H NMR (CDCl₃, 400 MHz) δ 8.81 (s, 1H), 3.47 (m, 1H), 3.20 (m,1H), 3.05 (m, 1H), 2.41 (m, 1H), 1.86 (m, 3H), 1.47 (m, 3H).

Step 6:

To a solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.5 g,14.8 mmol) in CHCl₃ (60 mL) was added MCPBA (8.30 g, 37.0 mmol) in threeportions. The mixture was stirred at room temperature for 2 days. Themixture was cooled to 0° C. and to this was added dropwise Na₂S₂O₃ (10g) in water (60 mL), followed by Na₂CO₃ (6 g) in water (20 mL). Thereaction mixture was stirred for 20 minutes. The aqueous phase wasextracted with CHCl₃ (2×200 mL), and the combined organic phases wereconcentrated at low temperature (<25° C.). The residue was purified bysilica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) togive (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide(1.45 g, 53%). ¹H NMR (CDCl₃, 400 MHz) δ 8.66 (s, 1H), 3.50 (m, 1H),3.20 (m, 2H), 2.44 (m, 1H), 1.90 (m, 1H), 1.37 (d, J=7.2 Hz, 3H).

Step 7:

A solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide (1.45g, 7.85 mmol) in acetic anhydride (20 mL) was heated to 110° C. for 2hours. After cooling, excess solvent was removed under vacuum. Theresidue was purified by silica gel chromatography, eluting withHexane/ethyl acetate (3:1) to give(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (1.25 g, 70%). ¹H NMR (CDCl₃, 400 MHz) δ 8.92 (m, 1H), 6.30-6.03(m, 1H), 3.60-3.30 (m, 1H), 2.84 (m, 1H), 2.40-2.20 (m, 1H), 2.15 (d,J=6 Hz, 2H), 1.75 (m, 2H), 1.47 (d, J=6.8, 2H), 1.38 (d, J=7.2, 1H). MS(APCI+) [M+H] ⁺227.

Step 8:

To a solution of(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (0.5 g, 2.2 mmol) in NMP (10 mL) was added 1-Boc-piperazine (0.9g, 4.8 mmol). The reaction mixture was heated to 110° C. for 12 hours.After cooling, the reaction mixture was diluted with ethyl acetate (200mL) and washed with water (6×100 mL). The organic phase was dried andconcentrated. The residue was purified by silica gel chromatography,eluting with ethyl acetate to give tert-butyl4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.6 g, 72%). ¹H NMR (CDCl₃, 400 MHz) δ 8.60 (d, 1H), 6.05-5.90 (m, 1H),3.80-3.30 (m, 9H), 2.84 (m, 1H), 2.20 (m, 1H), 1.49 (s, 9H), 1.29-1.20(m, 3H). MS (APCI+) [M+H] ⁺377. The resulting mixture of thediastereomers was purified by chiral separation HPLC (Chiralcel ODHcolumn, 250×20 mm, Hexane/EtOH 60:40, 21 mL/min). The first peak(RT=3.73 min) gave the tert-butyl4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.144 g, 24%). The second peak (RT=5.66 min) gave the tert-butyl4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.172 g, 29%). MS (APCI+) [M+H] ⁺377.

Step 9:

To a solution of tert-butyl4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.144 g, 0.383 mmol) in THF (4 mL) was added LiOH (3M, 2 mL). Themixture was stirred at room temperature for 6 hours and then quenchedwith 2N HCl (3 mL). The solvent was removed and the residue was purifiedby silica gel chromatography, eluting with ethyl acetate to givetert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(89 mg, 70%). %). ¹H NMR (CDCl₃, 400 MHz) δ 8.52 (s, 1H), 5.48 (br, 1H),5.14 (m, 1H), 3.82-3.40 (m, 9H), 2.20 (m, 2H), 1.49 (s, 9H), 1.19 (d,J=6.8 Hz, 3H). MS (APCI+) [M+H] ⁺335.

Step 10:

tert-Butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylatewas treated with HCl (4M in dioxane, 2 mL) in DCM (5 mL) for 6 hours togive(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride. MS (APCI+) [M+H] ⁺235.

Step 11:

Methyl 2-(4-chlorophenyl)acrylate (1.00 g, 5.09 mmol) was added as asolution in 2.5 mL of THF to a stirring solution of i-PrNH₂ (650 uL,7.63 mmol) in 10 mL of THF. The reaction was allowed to stir at roomtemperature overnight to completion by LCMS analysis. The solvent wasremoved under reduced pressure to give methyl2-(4-chlorophenyl)-3-(isopropylamino)propanoate (LCMS (APCI⁺) [M−Boc+H]⁺256.1, Rt: 1.97 min), which was re-dissolved in 15 mL of DCM at roomtemperature. The Boc2O (1.29 mL, 5.59 mmol) was added to the stirringamine via pipette followed by a catalytic amount (1 mg) of DMAP. Thereaction was allowed to stir overnight to completion by LCMS and TLCanalysis of the mixture. The solution was concentrated in vacuo toafford methyl3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate asan oily residue (LCMS (APCI⁺) [M−Boc+H]⁺ 256.1, Rt: 4.13 min) which wasre-dissolved in 12.0 mL of THF and 4.0 mL of water. The solution wastreated with LiOH—H₂O (1.07 g, 25.4 mmol) and allowed to stir for 4hours to completion by LCMS analysis. The solution was diluted withwater and washed with diethyl ether (discarded). The aqueous was treatedwith 1M HCl solution until pH 2-3 and extracted with ethyl acetateseveral times. The organics were combined, washed with brine, separated,dried over MgSO₄, filtered, and concentrated in vacuo to afford3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acidas a colorless oil (1.04 g, 60%). LCMS (APCI⁺) [M−Boc+H]⁺ 242.0.

Step 12:

To a solution of(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (41 mg, 0.13 mmol) and3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid(46 mg, 0.13 mmol) in DCM (10 mL) and triethylamine (1 mL) was addedHBTU (51 mg, 0.13 mmol). The reaction mixture was stirred at roomtemperature for 1 hour. The solvent was removed and the residue waspurified by silica gel chromatography, eluting with ethylacetate-DCM/MeOH (20:1) to give tert-butyl2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate(58 mg, 78%). ¹H NMR (CDCl₃, 400 MHz) δ 8.49 (s, 1H), 7.30-7.22 (m, 4H),5.11 (m, 1H), 3.80-3.40 (m, 13H), 2.20-2.10 (m, 2H), 1.48 (s, 9H), 1.14(m, 3H), 1.03 (m, 3H), 0.68 (m, 3H). MS (APCI+) [M+H] ⁺559.

Step 13:

Treatment of tert-butyl2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamatewith HCl (4M in dioxane, 2 mL) in DCM (5 mL) for 6 hours to give2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onedihydrochloride. ¹H NMR (D₂O, 400 MHz) δ 8.36-8.35 (m, 1H), 7.36-7.35(d, J=8.0 Hz, 2H), 7.22-7.20 (d, J=8.0 Hz, 2H), 5.23-5.10 (m, 1H),4.36-4.33 (m, 1H), 3.96-3.00 (m, 12H), 2.17-2.13 (m, 1H), 2.06-2.00 (m,1H), 1.20-1.17 (m, 6H), 1.08-0.97 (m, 3H). MS (APCI+) [M+H] ⁺459.

Example 2

Preparation of(R)-2-amino-3-(4-chlorophenyl)-1-((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-onedihydrochloride

Step 1:

To a solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.5 g,14.8 mmol) in CHCl₃ (60 mL) was added MCPBA (8.30 g, 37.0 mmol) in threeportions. The mixture was stirred at room temperature for 2 days. Themixture was cooled to 0° C. and to this was added dropwise Na₂S₂O₃ (10g) in water (60 mL), followed by Na₂CO₃ (6 g) in water (20 mL). Thereaction mixture was stirred for 20 minutes. The aqueous phase wasextracted with CHCl₃ (2×200 mL), and the combined organic phases wereconcentrated at low temperature (<25° C.). The residue was purified bysilica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) togive (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide(1.45 g, 53%). ¹H NMR (CDCl₃, 400 MHz) δ 8.66 (s, 1H), 3.50 (m, 1H),3.20 (m, 2H), 2.44 (m, 1H), 1.90 (m, 1H), 1.37 (d, J=7.2 Hz, 3H).

Step 2:

A solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide (1.45g, 7.85 mmol) in acetic anhydride (20 mL) was heated to 110° C. for 2hours. After cooling, excess solvent was removed under vacuum. Theresidue was purified by silica gel chromatography, eluting withHexane/ethyl acetate (3:1) to give(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (1.25 g, 70%). ¹H NMR (CDCl₃, 400 MHz) δ 8.92 (m, 1H), 6.30-6.03(m, 1H), 3.60-3.30 (m, 1H), 2.84 (m, 1H), 2.40-2.20 (m, 1H), 2.15 (d,J=6 Hz, 2H), 1.75 (m, 2H), 1.47 (d, J=6.8, 2H), 1.38 (d, J=7.2, 1H). MS(APCI+) [M+H] ⁺227.

Step 3:

To a solution of(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (0.75 g, 3.3 mmol) in NMP (10 mL) was added (S)-tert-butyl3-methylpiperazine-1-carboxylate (1.0 g, 5.0 mmol). The mixture washeated to 125° C. for 60 hours. After cooling, the mixture was dilutedwith ethyl acetate (200 mL) and washed with water (6×100 mL). Theorganic phase was dried and concentrated. The residue was purified bysilica gel chromatography, eluting with ethyl acetate to give(S)-tert-butyl4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.775 g, 60%). ¹H NMR (CDCl₃, 400 MHz) δ 8.60-8.59 (d, 1H), 6.07-5.89(m, 1H), 4.73-4.60 (m, 1H), 4.30-3.80 (m, 3H), 3.60-3.35 (m, 1H), 3.22(m, 1H), 3.02 (br, 1H), 2.78 (m, 1H), 2.35-1.60 (m, 5H), 1.49 (s, 9H),1.32-1.20 (m, 6H). MS (APCI+) [M+H] ⁺391. The resulting mixture ofdiastereomers was purified by chiral separation by HPLC (Chiralcel ODHcolumn, 250×20 mm, 15 mL/min, Hexane/EtOH 50:50). The first peak(RT=3.864 min) gave (S)-tert-butyl4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.281 g, 36%) and the second peak (RT=5.064 min) gave (S)-tert-butyl4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.389 g, 50%).

Step 4:

To a solution of the (S)-tert-butyl4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.281 g, 0.72 mmol) in THF (5 mL) was added LiOH (3M, 2 mL). Themixture was stirred at room temperature for 6 hours and then quenchedwith 2N HCl (3 mL). The solvent was removed and the residue was purifiedby silica gel chromatography, eluting with ethyl acetate to give(S)-tert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.206 g, 82%). ¹H NMR (CDCl₃, 400 MHz) δ 8.52 (s, 1H), 5.12 (m, 1H),4.76 (br, 1H), 4.30-3.80 (m, 3H), 3.52 (m, 1H), 3.26 (m, 1H), 3.03 (br,1H), 2.20 (m, 1H), 1.49 (s, 9H), 1.30-1.10 (m, 6H). MS (APCI+) [M+H]⁺349.

Step 5:

T a solution of the (S)-tert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.106 g, 0.304 mmol) in DCM (20 mL) was added HCl (4M in dioxane, 4mL). The mixture was stirred at room temperature overnight. The solventwas removed to afford(5R,7R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (0.098 g, 99%). MS (APCI+) [M+H] ⁺249.

Step 6:

To a solution of the(5R,7R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (33 mg, 0.10 mmol) and(R)-2-(tert-butoxycarbonyl)-3-(4-chlorophenyl)propanoic acid (31 mg,0.10 mmol) in DCM (5 mL) and triethylamine (1 mL) was added HBTU (39 mg,0.1 mmol). The mixture was stirred at room temperature for 1 hour. Thesolvent was removed and the residue was purified by silica gelchromatography, eluting with DCM/MeOH (20:1) to give tert-butyl(R)-3-(4-chlorophenyl)-1-((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-1-oxopropan-2-ylcarbamate(45 mg, 83%). ¹H NMR (CDCl₃, 400 MHz) δ 8.53 (s, 1H), 7.25-7.10 (m, 4H),5.60-5.30 (m, 1H), 5.20-4.60 (m, 3H), 4.50-4.00 (m, 2H), 3.90-3.60 (m,4H), 3.58-2.90 (m, 3H), 2.17 (m, 1H), 1.46-1.30 (m, 9H), 1.28-0.90 (m,6H). MS (APCI+) [M+H] ⁺531.

Step 7:

Treatment of tert-butyl(R)-3-(4-chlorophenyl)-1-((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-1-oxopropan-2-ylcarbamatewith HCl (4M in dioxane, 2 mL) in DCM (5 mL) for 6 hours gave the(R)-2-amino-3-(4-chlorophenyl)-1-((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-onedihydrochloride. ¹H NMR (D₂O, 400 MHz) δ 8.53-8.40 (m, 1H), 7.40-7.10(m, 4H), 5.35-5.30 (m, 1H), 4.05-3.95 (m, 1 h), 3.70-3.40 (m, 5H),3.20-2.90 (m, 4H), 2.40-2.20 (m, 2H), 2.04-1.98 (m, 1H), 1.20-0.95 (m,6H). MS (APCI+) [M+H] ⁺431.

Example 3

Preparation of(R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-onedihydrochloride

Step 1:

To a solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.5 g,14.8 mmol) in CHCl₃ (60 mL) was added MCPBA (8.30 g, 37.0 mmol) in threeportions. The mixture was stirred at room temperature for 2 days. Themixture was cooled to 0° C. and to this was added dropwise Na₂S₂O₃ (10g) in water (60 mL), followed by Na₂CO₃ (6 g) in water (20 mL). Thereaction mixture was stirred for 20 minutes. The aqueous phase wasextracted with CHCl₃ (2×200 mL), and the combined organic phases wereconcentrated at low temperature (<25° C.). The residue was purified bysilica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) togive (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide(1.45 g, 53%). ¹H NMR (CDCl₃, 400 MHz) δ 8.66 (s, 1H), 3.50 (m, 1H),3.20 (m, 2H), 2.44 (m, 1H), 1.90 (m, 1H), 1.37 (d, J=7.2 Hz, 3H).

Step 2:

A solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide (1.45g, 7.85 mmol) in acetic anhydride (20 mL) was heated to 110° C. for 2hours. After cooling, excess solvent was removed under vacuum. Theresidue was purified by silica gel chromatography, eluting withHexane/ethyl acetate (3:1) to give(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (1.25 g, 70%). ¹H NMR (CDCl₃, 400 MHz) δ 8.92 (m, 1H), 6.30-6.03(m, 1H), 3.60-3.30 (m, 1H), 2.84 (m, 1H), 2.40-2.20 (m, 1H), 2.15 (d,J=6 Hz, 2H), 1.75 (m, 2H), 1.47 (d, J=6.8, 2H), 1.38 (d, J=7.2, 1H). MS(APCI+) [M+H] ⁺227.

Step 3:

To a solution of(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (0.75 g, 3.3 mmol) in NMP (10 mL) was added (S)-tert-butyl3-methylpiperazine-1-carboxylate (1.0 g, 5.0 mmol). The mixture washeated to 125° C. for 60 hours. After cooling, the mixture was dilutedwith ethyl acetate (200 mL) and washed with water (6×100 mL). Theorganic phase was dried and concentrated. The residue was purified bysilica gel chromatography, eluting with ethyl acetate to give(S)-tert-butyl4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.775 g, 60%). ¹H NMR (CDCl₃, 400 MHz) δ 8.60-8.59 (d, 1H), 6.07-5.89(m, 1H), 4.73-4.60 (m, 1H), 4.30-3.80 (m, 3H), 3.60-3.35 (m, 1H), 3.22(m, 1H), 3.02 (br, 1H), 2.78 (m, 1H), 2.35-1.60 (m, 5H), 1.49 (s, 9H),1.32-1.20 (m, 6H). MS (APCI+) [M+H] ⁺391. The resulting mixture ofdiastereomers was purified by chiral separation by HPLC (Chiralcel ODHcolumn, 250×20 mm, 15 mL/min, Hexane/EtOH 50:50). The first peak(RT=3.864 min) gave (S)-tert-butyl4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.281 g, 36%) and the second peak (RT=5.064 min) gave (S)-tert-butyl4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.389 g, 50%). Treatment of the (S)-tert-butyl4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylatewith HCl in dioxane (4M, 2 ml) gave the(5R,7R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride in quantitative yield.

Step 4:

To a solution of(5R,7R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (33 mg, 0.10 mmol) and(R)-2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)propanoic acid(33 mg, 0.10 mmol) in DCM (5 mL) and triethylamine (1 mL) was added HBTU(39 mg, 0.1 mmol). The mixture was stirred at room temperature for 1hour. The solvent was removed and the residue was purified by silica gelchromatography, eluting with DCM/MeOH (20:1) to give tert-butyl(R)-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-1-oxopropan-2-ylcarbamate(44 mg, 78%). ¹H NMR (CDCl₃, 400 MHz) δ 8.53 (s, 1H), 7.31-6.88 (m, 3H),5.60-5.30 (m, 1H), 5.13 (m, 3H), 4.90-4.70 (m, 2H), 4.60-4.00 (m, 2H),3.90-2.85 (m, 7H), 2.19 (m, 1H), 1.40 (m, 9H), 1.28-0.98 (m, 6H). MS(APCI+) [M+H] ⁺549.

Step 5:

Treatment of tert-butyl(R)-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-1-oxopropan-2-ylcarbamatewith HCl (4M in dioxane, 2 mL) in DCM (5 mL) for 6 hours gave(R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-onedihydrochloride. ¹H NMR (D₂O, 400 MHz) δ 8.51-8.40 (m, 1H), 7.29-7.24(m, 1H), 7.08-7.08 (d, J=10 Hz, 1H), 6.95-6.93 (d, J=8.4 Hz, 1H),5.36-5.32 (m, 1H), 4.18-3.98 (m, 2H), 3.75-3.50 (m, 5H), 3.20-2.97 (m,4H), 2.60-2.50 (m, 1H), 2.30-2.20 (m, 1H), 2.05-1.98 (m, 1H). 1.14-1.12(d, J=6.4 Hz, 3H), 0.98-0.96 (d, J=6.8 Hz, 3H). MS (APCI+) [M+H] ⁺449.

Example 4

Preparation of(R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((5R,7R)-7-methoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-onedihydrochloride

Step 1

1,1,3,3-Tetramethylguanidine (2.11 ml, 16.8 mmol) was added to a 0° C.solution of methyl2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)-acetate (5.00 g, 16.8mmol) in DCM (70 mL). The reaction mixture was stirred at 0° C. for 30minutes. Then a solution of 4-chloro-3-fluorobenzaldehyde (2.67 g, 16.8mmol) in DCM (10 mL) was added by syringe. The reaction mixture wasstirred for 10 minutes, then warmed to room temperature and stirred foranother 1 hour. H₂O was then added, and the mixture was extracted withDCM. The combined extracts were dried (Na₂SO₄), filtered, andconcentrated. The resulting solids were recrystallized from IPA to give(Z)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)acrylate(3.76 g, 67.8% yield) as a white powder (2 crops). LCMS (APCI⁻) m/z 328[M−H]⁻.

Step 2:

(Z)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)acrylate(200 mg) and ca. Rh—(R,R)-[Et-DuPhos(COD)]OTf (4 mg) in 1:1 MeOH:EtOAc(3 mL; degassed 1 h with N₂ prior to use) was dissolved in 8 ArgonautEndeavor™ reaction tubes. The reaction mixtures were put on theEndeavor™ under 40 psi H₂ and stirred for 12 hours at room temperature.All of the reaction mixtures were then combined and concentrated to give(R)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)propanoate(1.52 g, 94.4% yield) as a pale yellow solid, which was used withoutfurther purification in next step.

Step 3:

LiOH—H₂O (0.6246 g, 14.88 mmol) was added to a solution of (R)-methyl2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)propanoate (1.646 g,4.961 mmol) in 1:1 THF:H₂O (26 mL). The reaction mixture was stirred atroom temperature for 2 hours, after which it was diluted with H₂O andwashed with EtOAc. The aqueous layer was then acidified with solid KHSO₄and extracted with DCM. The combined extracts were dried (Na₂SO₄),filtered, concentrated, and then re-concentrated from DCM/hexanes togive (R)-2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)-propanoicacid (1.31 g, 83.10% yield) as a white powder. LCMS (APCI) m/z 316[M−H]⁻.

Step 4:

To a solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.5 g,14.8 mmol) in CHCl₃ (60 mL) was added MCPBA (8.30 g, 37.0 mmol) in threeportions. The mixture was stirred at room temperature for 2 days. Themixture was cooled to 0° C. and to this was added dropwise Na₂S₂O₃ (10g) in water (60 mL), followed by Na₂CO₃ (6 g) in water (20 mL). Thereaction mixture was stirred for 20 minutes. The aqueous phase wasextracted with CHCl₃ (2×200 mL), and the combined organic phases wereconcentrated at low temperature (<25° C.). The residue was purified bysilica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) togive (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide(1.45 g, 53%). ¹H NMR (CDCl₃, 400 MHz) δ 8.66 (s, 1H), 3.50 (m, 1H),3.20 (m, 2H), 2.44 (m, 1H), 1.90 (m, 1H), 1.37 (d, J=7.2 Hz, 3H).

Step 5:

A solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide (1.45g, 7.85 mmol) in acetic anhydride (20 mL) was heated to 110° C. for 2hours. After cooling, excess solvent was removed under vacuum. Theresidue was purified by silica gel chromatography, eluting withHexane/ethyl acetate (3:1) to give(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (1.25 g, 70%). ¹H NMR (CDCl₃, 400 MHz) δ 8.92 (m, 1H), 6.30-6.03(m, 1H), 3.60-3.30 (m, 1H), 2.84 (m, 1H), 2.40-2.20 (m, 1H), 2.15 (d,J=6 Hz, 2H), 1.75 (m, 2H), 1.47 (d, J=6.8, 2H), 1.38 (d, J=7.2, 1H). MS(APCI+) [M+H] ⁺227.

Step 6:

To a solution of(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (0.75 g, 3.3 mmol) in NMP (10 mL) was added (S)-tert-butyl3-methylpiperazine-1-carboxylate (1.0 g, 5.0 mmol). The mixture washeated to 125° C. for 60 hours. After cooling, the mixture was dilutedwith ethyl acetate (200 mL) and washed with water (6×100 mL). Theorganic phase was dried and concentrated. The residue was purified bysilica gel chromatography, eluting with ethyl acetate to give(S)-tert-butyl4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.775 g, 60%). ¹H NMR (CDCl₃, 400 MHz) δ 8.60-8.59 (d, 1H), 6.07-5.89(m, 1H), 4.73-4.60 (m, 1H), 4.30-3.80 (m, 3H), 3.60-3.35 (m, 1H), 3.22(m, 1H), 3.02 (br, 1H), 2.78 (m, 1H), 2.35-1.60 (m, 5H), 1.49 (s, 9H),1.32-1.20 (m, 6H). MS (APCI+) [M+H] ⁺391. The resulting mixture ofdiastereomers was purified by chiral separation by HPLC (Chiralcel ODHcolumn, 250×20 mm, 15 mL/min, Hexane/EtOH 50:50). The first peak(RT=3.864 min) gave (S)-tert-butyl4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.281 g, 36%) and the second peak (RT=5.064 min) gave (S)-tert-butyl4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.389 g, 50%).

Step 7:

To a solution of (S)-tert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.098 g, 0.28 mmol) in THF (10 mL) were added NaH (60%, 50 mg, 1.25mmol) and MeI (0.08 mL, 1.28 mmol). The mixture was stirred at roomtemperature overnight. The solution was removed and the residue waspurified by silica gel chromatography, eluting with ethyl acetate togive (S)-tert-butyl4-((5R,7R)-7-methoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(0.056 g, 55%). ¹H NMR (CDCl₃, 400 MHz) δ 8.56 (s, 1H), 4.66 (m, 2H),4.30-3.80 (m, 3H), 3.55 (s, 3H), 3.54-2.90 (m, 4H), 2.25 (m, 1H), 1.98(m, 1H), 1.49 (s, 9H), 1.24 (d, J=12.4 Hz, 3H), 1.13 (d, J=7.2 Hz, 3H).MS (APCI+) [M+H] ⁺363.

Step 8:

Treatment of (S)-tert-butyl4-((5R,7R)-7-methoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylatewith HCl (4M in dioxane, 4 mL) in DCM (20 mL) for 10 hours gave(5R,7R)-7-methoxy-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidinedihydrochloride. MS (APCI+) [M+H] ⁺263.

Step 9:

To a solution of(5R,7R)-7-methoxy-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidinedihydrochloride (52 mg, 0.16 mmol) and(R)-2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)propanoic acid(49 mg, 0.16 mmol) in DCM (20 mL) and triethylamine (2 mL) was addedHBTU (59 mg, 0.16 mmol). The mixture was stirred at room temperature for1 hour. The solvent was removed and the residue was purified by silicagel chromatography, eluting with ethyl acetate to give tert-butyl(R)-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((5R,7R)-7-methoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-1-oxopropan-2-ylcarbamate(70 mg, 80%). ¹H NMR (CDCl₃, 400 MHz) δ 8.57 (s, 1H), 7.28 (m, 1H),7.05-6.90 (m, 2H), 5.40-5.05 (m, 1H), 4.90-4.30 (m, 4H), 4.10-3.60 (m,3H), 3.55 (s, 3H), 3.53-2.82 (m, 4H), 2.26 (m, 1H), 2.00 (m, 1H). 1.42(m, 9H), 1.30-1.00 (m, 6H). MS (APCI+) [M+H] ⁺563.

Step 10:

Treatment of tert-butyl(R)-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((5R,7R)-7-methoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-1-oxopropan-2-ylcarbamatewith HCl (4M in dioxane, 2 mL) in DCM (10 mL) for 10 hours gave(R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((5R,7R)-7-methoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-onedihydrochloride. ¹H NMR (D₂O, 400 MHz) δ 8.51-8.40 (m, 1H), 7.29-7.21(m, 1H), 7.10-7.00 (m, 1H), 6.98-6.90 (m, 1H), 5.15-5.02 (m, 1H), 4.90(m, 1H), 4.70-4.67 (m, 1H), 4.08-3.98 (m, 2H), 3.75-3.50 (m, 4H), 3.37(s, 3H), 3.20-2.97 (m, 4H), 2.60-2.50 (m, 1H), 2.30-2.20 (m, 1H),2.10-2.01 (m, 1H). 1.25-0.95 (m, 6H). MS (APCI+) [M+H] ⁺463.

Example 5

Preparation of(S)-3-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-onedihydrochloride

Step 1:

To a 1 L round-bottom flask were added (R)-(+)-Pulegone (76.12 g, 0.5mmol), anhydrous NaHCO₃ (12.5 g) and anhydrous ether (500 mL). Thereaction mixture was cooled with ice-bath under nitrogen. The bromine(25.62 mL, 0.5 mmol) was added dropwise over 30 minutes. The mixture wasfiltered and carefully added to NaOEt (21%, 412 mL, 1.11 mmol) in anice-cooled bath. The mixture was stirred at room temperature overnightand then 1 L of 5% HCl and 300 mL of ether were added. The aqueous phasewas extracted with ether (2×300 mL). The combined organic phase waswashed with water, dried and concentrated. The residue was added to awarmed solution of semicarbazide hydrochloride (37.5 g) and NaOAc (37.5g) in water (300 mL), and then boiling ethanol (300 mL) was added togive a clear solution. The mixture was refluxed for 2.5 hours and thenstirred at room temperature overnight. The mixture was treated with 1 Lof water and 300 mL of ether. The aqueous phase was extracted with ether(2×300 mL). The combined organic phase was washed with water, dried andconcentrated. The residue was purified by vacuum distillation (73-76° C.at 0.8 mm Hg) to give (2R)-ethyl2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (63 g, 64%). ¹H NMR(CDCl₃, 400 MHz) δ 4.13 (m, 2H), 3.38 (d, J=16 Hz, 0.5H), 2.93 (m,0.5H), 2.50-2.17 (m, 2H), 1.98 (m, 1H), 1.76 (m, 1H), 1.23 (m, 6H), 1.05(m, 6H).

Step 2:

(2R)-Ethyl 2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (24 g,0.122 mol) in ethyl acetate (100 mL) was cooled to −68° C. with dryice/isopropanol. Ozonized oxygen (5-7 ft³ h⁻¹ of O₂) was bubbled throughthe solution for 3.5 hours. The reaction mixture was flushed withnitrogen at room temperature until the color disappeared. The ethylacetate was removed under vacuum and the residue was dissolved in 150 mLof acetic acid and cooled by ice water, and zinc powder (45 g) wasadded. The solution was stirred for 30 minutes and then filtered. Thefiltrate was neutralized with 2N NaOH (1.3 L) and NaHCO₃. The aqueousphase was extracted with ether (3×200 mL). The organic phase wascombined, washed with water, dried and concentrated to afford (2R)-ethyl2-methyl-5-oxocyclopentanecarboxylate (20 g, 96%). ¹H NMR (CDCl₃, 400MHz) δ 4.21 (m, 2H), 2.77 (d, J=11.2 Hz, 1H), 2.60 (m, 1H), 2.50-2.10(m, 3H), 1.42 (m, 1H), 1.33 (m, 3H), 1.23 (m, 3H).

Step 3:

To a solution of a mixture of (2R)-ethyl2-methyl-5-oxocyclopentanecarboxylate (20 g, 117.5 mmol) and thiourea(9.2 g, 120.9 mmol) in ethanol (100 mL) was added KOH (8.3 g, 147.9mmol) in water (60 mL). The mixture was refluxed for 10 hours. Aftercooling, the solvent was removed and the residue was neutralized withconcentrated HCl (12 mL) at 0° C. and then extracted with DCM (3×150mL). The solvent was removed and the residue was purified by silica gelchromatography, eluting with Hexane/ethyl acetate (2:1) to give(R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12g, 56%). MS (APCI+) [M+H] ⁺183.

Step 4:

To a suspension of(R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12g, 65.8 mmol) in distilled water (100 mL) was added Raney Nickel (15 g)and NH₄OH (20 mL). The mixture was refluxed for 3 hours then filtered,and the filtrate was concentrated to afford(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.89 g, 99%).MS (APCI+) [M+H] ⁺151.

Step 5:

A mixture of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol(5.8 g, 38.62 mmol) in POCl₃ (20 mL) was refluxed for 5 minutes. ExcessPOCl₃ was removed under vacuum and the residue was dissolved in DCM (50mL). The mixture was then added to saturated NaHCO₃ (200 mL). Theaqueous phase was extracted with DCM (3×100 mL), and the combinedorganic phases were dried and concentrated. The residue was purified bysilica gel chromatography, eluting with ethyl acetate to give(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (3.18 g,49%). ¹H NMR (CDCl₃, 400 MHz) δ 8.81 (s, 1H), 3.47 (m, 1H), 3.20 (m,1H), 3.05 (m, 1H), 2.41 (m, 1H), 1.86 (m, 3H), 1.47 (m, 3H).

Step 6:

To a solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.5 g,14.8 mmol) in CHCl₃ (60 mL) was added MCPBA (8.30 g, 37.0 mmol) in threeportions. The mixture was stirred at room temperature for 2 days. Themixture was cooled to 0° C. and to this was added dropwise Na₂S₂O₃ (10g) in water (60 mL), followed by Na₂CO₃ (6 g) in water (20 mL). Thereaction mixture was stirred for 20 minutes. The aqueous phase wasextracted with CHCl₃ (2×200 mL), and the combined organic phases wereconcentrated at low temperature (<25° C.). The residue was purified bysilica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) togive (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide(1.45 g, 53%). ¹H NMR (CDCl₃, 400 MHz) δ 8.66 (s, 1H), 3.50 (m, 1H),3.20 (m, 2H), 2.44 (m, 1H), 1.90 (m, 1H), 1.37 (d, J=7.2 Hz, 3H).

Step 7:

A solution of(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide (1.45g, 7.85 mmol) in acetic anhydride (20 mL) was heated to 110° C. for 2hours. After cooling, excess solvent was removed under vacuum. Theresidue was purified by silica gel chromatography, eluting withHexane/ethyl acetate (3:1) to give(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (1.25 g, 70%). ¹H NMR (CDCl₃, 400 MHz) δ 8.92 (m, 1H), 6.30-6.03(m, 1H), 3.60-3.30 (m, 1H), 2.84 (m, 1H), 2.40-2.20 (m, 1H), 2.15 (d,J=6 Hz, 2H), 1.75 (m, 2H), 1.47 (d, J=6.8, 2H), 1.38 (d, J=7.2, 1H). MS(APCI+) [M+H] ⁺227.

Step 8:

To a solution of(5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (0.5 g, 2.2 mmol) in NMP (10 mL) was added 1-Boc-piperazine (0.9g, 4.8 mmol). The reaction mixture was heated to 110° C. for 12 hours.After cooling, the reaction mixture was diluted with ethyl acetate (200mL) and washed with water (6×100 mL). The organic phase was dried andconcentrated. The residue was purified by silica gel chromatography,eluting with ethyl acetate to give tert-butyl4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.6 g, 72%). ¹H NMR (CDCl₃, 400 MHz) δ 8.60 (d, 1H), 6.05-5.90 (m, 1H),3.80-3.30 (m, 9H), 2.84 (m, 1H), 2.20- (m, 1H), 1.49 (s, 9H), 1.29-1.20(m, 3H). MS (APCI+) [M+H] ⁺377. The resulting mixture of thediastereomers was purified by chiral separation HPLC (Chiralcel ODHcolumn, 250×20 mm, Hexane/EtOH 60:40, 21 mL/min). The first peak(RT=3.73 min) gave the tert-butyl4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.144 g, 24%). The second peak (RT=5.66 min) gave the tert-butyl4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.172 g, 29%). MS (APCI+) [M+H] ⁺377.

Step 9:

To a solution of tert-butyl4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.144 g, 0.383 mmol) in THF (4 mL) was added LiOH (3M, 2 mL). Themixture was stirred at room temperature for 6 hours and then quenchedwith 2N HCl (3 mL). The solvent was removed and the residue was purifiedby silica gel chromatography, eluting with ethyl acetate to givetert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(89 mg, 70%). %). ¹H NMR (CDCl₃, 400 MHz) δ 8.52 (s, 1H), 5.48 (br, 1H),5.14 (m, 1H), 3.82-3.40 (m, 9H), 2.20 (m, 2H), 1.49 (s, 9H), 1.19 (d,J=6.8 Hz, 3H). MS (APCI+) [M+H] ⁺335.

Step 10:

tert-Butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylatewas treated with HCl (4M in dioxane, 2 mL) in DCM (5 mL) for 6 hours togive(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride. MS (APCI+) [M+H] ⁺235.

Step 11:

Tert-butyl 2,4-dimethoxybenzylcarbamate (3.96 g, 14.8 mmol) wasdissolved in THF (74 mL) and cooled to −78° C. The solution was treatedwith butyl lithium (7.44 mL, 16.3 mmol) dropwise over a five minuteperiod to afford a pale-yellow solution. The solution was allowed tostir for 15 minutes before the chloro(methoxy)methane (1.35 mL, 17.8mmol) was added dropwise (neat). The reaction was stirred at −78° C. for10 minutes, then allowed to warm slowly to ambient temperatureovernight. The reaction was concentrated in vacuo to afford a yellow gelwhich was partitioned between half-saturated NH₄Cl solution and ether.The aqueous layer was extracted once, and the organics were combined.The organic layer was washed with water, then brine, separated, driedover Na₂SO₄, filtered, and concentrated in vacuo. ¹H NMR supports thedesired near-pure (>90%) tert-butyl2,4-dimethoxybenzyl(methoxymethyl)carbamate (4.81 g, 104% yield) as apale-yellow oil which was used without purification.

Step 12: (R)-4-benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (3.00g, 9.10 mmol) was dissolved in DCM (91 mL) and cooled to −78° C. A 1Mtoluene solution of TiCl₄ (11.4 mL, 11.4 mmol) was added to the solutionfollowed by DIEA (1.66 mL, 9.55 mmol) to afford a dark purple reaction.This was allowed to stir for 15 minutes before the tert-butyl2,4-dimethoxybenzyl(methoxymethyl)carbamate (3.40 g, 10.9 mmol) wasadded as a solution in DCM (10 mL) dropwise. The reaction was allowed tostir for 15 minutes at −78° C., then allowed to warm to −18° C. in abrine-ice bath for one hour. This reaction was allowed to warm slowly to0° C. over a 2.5 hour period. The reaction was then quenched with theaddition of saturated NH₄Cl solution (100 mL). The layers wereseparated, and the organic layers was extracted once with DCM. Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo to afford a yellow oil. The residue was purifiedby chromatography (silica gel eluted with 4:1 hexanes:ethyl acetate) toafford the pure material as a colorless oil tert-butyl2,4-dimethoxybenzyl((S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl)carbamate(4.07 g, 73.5% yield). This tert-butyl2,4-dimethoxybenzyl((S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl)carbamate(680 mg, 1.12 mmol) was dissolved in DCM (10.6 mL) and water (560 uL;19:1 DCM:water) at ambient temperature. The solution was treated withDDQ (380 mg, 1.67 mmol), and the reaction was allowed to stir for oneday to afford reaction completion by TLC and LCMS analysis. The reactionwas diluted with DCM and washed twice with half saturated NaHCO₃solution. The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo to afford a yellow-orange oil. The residue waspurified by chromatography (silica gel eluted with 9:1 hexanes:ethylacetate) to afford a mixture of the aldehyde by-product and tert-butyl(S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropylcarbamate(not separable) as a pale-yellow oil (729 mg combined mass). LC/MS(APCI+) m/z 359.1 [M−BOC+H]⁺.

Step 13:

35% H₂O₂ (0.240 mL, 2.91 mmol) was added to a solution of LiOH—H₂O(0.0978 g, 2.33 mmol) in 2:1 THF:H₂O (33 mL). The reaction mixture wasstirred at room temperature for 35 minutes, and then cooled to 0° C. Asolution containing a mixture of tert-butyl(S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropylcarbamate(0.535 g, 1.17 mmol) and 2,4-dimethoxybenzaldehyde (0.194 g, 1.17 mmol)in THF (7 mL) was added dropwise by addition funnel. The ice bath wasallowed to slowly warm, and the reaction mixture was stirred overnight.The reaction mixture was then cooled to 0° C., and 1M Na₂SO₃ (7 mL) wasadded. The mixture was stirred for 5 minutes, and then warmed to roomtemperature and stirred an additional 20 minutes. The reaction mixturewas then transferred to a separatory funnel and washed with ether (3×).The aqueous layer was acidified with KHSO₄(s), and the mixture wasextracted with DCM (2×). The combined extracts were dried (Na₂SO₄),filtered, and concentrated to give(S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.329g, 94.2% yield) as a white residue. LC/MS (APCI+) m/z 200 [M−BOC+H]⁺.

Step 14:

4M HCl/dioxane (5.49 ml, 22.0 mmol) was added to a solution of(S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.329g, 1.10 mmol) in 2:1 dioxane:DCM (10 mL). The reaction mixture wasstirred at room temperature overnight (16 hours), after which it wasconcentrated to ⅓ volume. The resulting cloudy mixture was diluted withether, and the mixture was concentrated again to ⅓ volume. The mixturewas diluted again with ether (20 mL), and the solids were isolated byfiltration through a medium frit funnel with nitrogen pressure, rinsedwith ether (5×10 mL), dried under nitrogen pressure, and dried in vacuoto give (S)-3-amino-2-(4-chlorophenyl)propanoic acid hydrochloride(0.199 g, 76.8% yield) as a white powder. HPLC >99 area % pure. LC/MS(APCI+) m/z 200.

Step 15:

Boc2O (0.368 g, 1.69 mmol) was added to a solution of(S)-3-amino-2-(4-chlorophenyl)propanoic acid hydrochloride (0.199 g,0.843 mmol) and tetramethylammonium hydroxide pentahydrate (0.382 g,2.11 mmol) in 10:1 MeCN:H₂O (7.7 mL). The reaction mixture was stirredovernight at room temperature (12 hours), after which the MeCN wasremoved on a rotary evaporator. The mixture was diluted with water andwashed with ether (2×). The aqeuous layer was acidified with KHSO₄(s),the mixture was extracted with DCM, and the combined extracts were dried(Na₂SO₄), filtered, and concentrated to give(S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.229g, 90.6% yield) as a foam. HPLC >99 area % pure. LC/MS (APCI+) m/z 200[M−BOC+H]⁺.

Step 16:

To a solution of(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (88 mg, 0.29 mmol) and(S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (86mg, 0.29 mmol) in DCM (10 mL) and Diisopropylethylamine (0.22 mL, 1.3mmol) was added HBTU (110 mg, 0.29 mmol). The reaction mixture wasstirred at room temperature for 1 hour. The solvent was removed and theresidue was dissolved in ethyl acetate (100 mL), washed with water (6×50ml). The organic phase was dried and concentrated to give tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate(116 mg, 78%). ¹H NMR (CDCl₃, 400 MHz) δ 8.51 (s, 1H), 7.34-7.20 (m,4H), 5.15-5.09 (m, 2H), 4.15-4.05 (m, 1H), 3.87-3.85 (m, 2H), 3.78-3.38(m, 7H), 3.22-3.19 (m, 1H), 2.20-2.10 (m, 2H), 1.48 (s, 9H), 1.41 (s,9H), 1.14-1.12 (d, J=7.2 Hz, 3H). MS (APCI+) [M+H] ⁺516.

Step 17:

Treatment of tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylcarbamatewith HCl (4M in dioxane, 2 mL) in DCM (5 mL) for 6 hours to give(S)-3-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-onedihydrochloride. ¹H NMR (D₂O, 400 MHz) δ 8.38 (s, 1H), 7.37-7.35 (d,J=8.4 Hz, 2H), 7.23-7.21 (d, J=8.4 Hz, 2H), 5.29-5.25 (m, 1H), 4.64 (s,9H), 4.31-4.28 (m, 1H), 4.11 (m, 1H), 3.88-3.79 (m, 2H), 3.70-3.20 (m,10H), 2.23-2.17 (m, 1H), 2.07-1.99 (m, 1H), 1.22-1.20 (m, 2H), 0.98-0.96(d, J=6.8 Hz, 2H). MS (APCI+) [M+H] ⁺416.

The following compounds have also been prepared according to theabove-described methods unless otherwise noted.

Example 6

(R)-2-amino-3-(4-chlorophenyl)-1-((S)-4-((S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.60-8.40 (m, 1H), 7.40-7.10 (m, 4H), 5.25-5.10(m, 1H), 4.00-2.90 (m, 14H), 2.52-2.40 (m, 1H), 1.95-1.80 (m, 1H),1.20-1.10 (m, 3H). MS (APCI+) [M+H] ⁺416.

Example 7

(R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.55-8.40 (m, 1H), 7.40-7.10 (m, 3H), 5.25-5.10(m, 1H), 4.00-2.90 (m, 14H), 2.52-2.40 (m, 1H), 1.95-1.80 (m, 1H),1.20-1.10 (m, 3H). MS (APCI+) [M+H] ⁺434.

Example 8

(2R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((3S)-4-((5R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.52-8.50 (m, 1H), 7.44-7.38 (m, 1H), 7.16-7.00(m, 2H), 5.15-5.10 (m, 1H), 4.22-4.10 (m, 1H), 3.90-3.00 (m, 9H),2.49-2.30 (m 2H), 1.60-1.50 (m, 1H), 1.18-0.95 (m, 6H). MS (APCI+) [M+H]⁺448.

Example 9

(2R)-2-amino-3-(4-chlorophenyl)-1-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.44 (s, 1H), 7.31-7.10 (m, 4H), 5.20-5.16 (m,1H), 4.00-3.90 (m, 1H), 3.82-2.90 (m, 12H), 2.60-2.50 (m, 1H), 1.90-1.80(m, 1H), 1.17-1.10 (m, 3H). MS (APCI+) [M+H] ⁺402.

Example 10

(R)-2-amino-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methoxyphenyl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.44 (s, 1H), 7.17-7.10 (m, 2H), 6.90-6.80 (m,2H), 5.31-5.26 (m, 1H), 4.15-4.05 (m, 1H), 3.80-2.90 (m, 11H), 2.68 (s,3H), 2.26-2.20 (m, 1H), 2.10-2.00 (m, 1H), 1.04-1.00 (m, 3H). MS (APCI+)[M+H] ⁺412.

Example 11

2-(4-chlorophenyl)-1-((S)-4-((R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-3-(isopropylamino)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.40-8.25 (m, 1H), 7.45-7.10 (m, 4H), 5.25-5.10(m, 1H), 4.40-4.19 (m, 1H), 3.80-2.80 (m, 12H), 2.55-2.40 (m, 1H),1.85-1.70 (m, 1H), 1.22-1.10 (m, 9H). MS (APCI+) [M+H] ⁺458.

Example 12

Preparation of2-(4-chlorophenyl)-1-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onedihydrochloride

Step 1:

To a solution of the methyl 2-oxocyclopentanecarboxylate (40 g, 281mmol) and thiourea (21 g, 281 mmol) in ethanol (200 ml) was added KOH(20 g, 356 mmol) in water (120 ml). The mixture was refluxed for 12hour. The solvent was removed and the residue was quenched withconcentrated HCl (25 mL). The precipitate was filtered, washed withwater and dried to afford the2-mercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12.5 g, 26%). MS(APCI+) [M+H] ⁺168.

Step 2:

To a solution of 2-mercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol(12.2 g, 72.5 mmol) in water (200 ml) was added Raney Ni (8 g, slurry inwater) and followed by concentrated ammonia solution (27 mmol). Themixture was refluxed for 6 hour. The catalyst was filtered off. Thesolvent was removed under vacuum to afford6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.87 g, 99%). ¹H NMR (CD₃OD,400 MHz) δ 8.07 (s, 1H), 2.89-2.85 (m, 2H), 2.80-2.76 (m, 2H), 2.23 (m,1H), 2.13-2.05 (m, 2H), 1.64 (m, 1H).

Step 3:

To a solution of 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (9.87 g,72.5 mmol) in DCE (200 ml) was added DIEA (15 mL, 86.1 mmol). Themixture was stirred at room temperature for 30 minutes and then addedPOCl₃ (15 mL, 163.9 mmol) was added slowly. The mixture was stirred atroom temperature for 1 hour and then refluxed for 12 hour. Aftercooling, the solvent was removed and the residue was dissolved in CHCl₃(200 ml). The mixture was basified by adding ice-cooled concentratedaqueous ammonia (15 mL). The organic phase was separated. The aqueousphase was washed with CHCl₃ (3×100 mL). The organic phase was combined,dried and concentrated. The residue was subject to chromatography onsilica gel, eluted by Hexanes/ethyl acetate (4:1) to afford4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.7 g, 51%). ¹H NMR(CDCl₃, 400 MHz) δ 8.76 (s, 1H), 3.12-3.01 (m, 4H), 2.23-2.14 (m, 2H).

Step 4:

To a solution of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.69g, 36.8 mmol) in chloroform (200 mL) was added MCPBA (19 g, 84.8 mmol)in chloroform (50 mL) dropwise. The mixture was stirred at roomtemperature for 16 hour. After cooling with ice-water, the mixture wasquenched with Na₂S₂O₃ (27.5 g) in water (110 mL) dropwise and followedby Na₂CO₃ (14 g) in water (52 mL) dropwise. The organic phase wasseparated and the aqueous phase was extracted with chloroform (3×200mL). The organic phase was dried and concentrated at low temperature(<25° C.). The residue was subject to chromatography on silica gel,eluting by ethyl acetate to afford4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (2.93 g, 47%).MS (APCI+) [M+H] ⁺171.

Step 5:

The solution of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide(2.93 g, 17.2 mmol) in acetic anhydride (50 mL) was added dropwise tothe acetic anhydride (50 mL) at 50° C. After addition, the mixture wasstirred at 110° C. for 2 hour. After cooling, the solvent was removedand the residue was treated with toluene and hexanes (1:1, 200 mL). Themixture was stirred and then the solvent was removed. The residue wassubject to chromatography on silica gel, eluted by hexanes/ethyl acetate(4:1-3:1) to afford the4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (2.3 g,63%). ¹H NMR (CDCl₃, 400 MHz) δ 8.92 (s, 1H), 6.20-6.16 (m, 1H),3.20-3.10 (m, 1H), 3.03-2.93 (m, 1H), 2.76-2.67 (m, 1H), 2.20-2.05 (m,4H).

Step 6:

To a solution of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ylacetate (1.15 g, 5.4 mmol) in NMP (4 mL) and TEA (0.5 mL) was added1-Boc-piperazine (1.05 g, 5.64 mmol). The mixture was microwaved at 100°C. for 30 minutes and then diluted with ethyl acetate (200 mL) andwashed with water (6×100 mL). The organic phase was dried andconcentrated. The residue was subject to chromatography on silica gel,eluting by hexanes/ethyl acetate (2:1-1:1) to afford the tert-butyl4-(7-acetoxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(1.47 g, 75%). ¹H NMR (CDCl₃, 400 MHz) δ 8.56 (s, 1H), 5.99-5.96 (m,1H), 3.78-3.73 (m, 2H), 3.53-3.50 (m, 2H), 3.15-3.07 (m, 1H), 2.99-2.92(m, 1H), 2.63-2.54 (m, 1H), 2.04-1.93 (m, 1H), 1.48 (s, 9H). MS (APCI+)[M+H] ⁺363.

Step 7:

To a solution of tert-butyl4-(7-acetoxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.43 g, 1.2 mmol) in THF (15 mL) was added LiOH (3M, 6 mL). The mixturewas stirred at room temperature overnight. The mixture was quenched with2N HCl (9 mL) and then extracted with DCM (3×100 mL). The organic phasewas dried and concentrated. The residue was subject to chromatography onsilica gel, eluted by DCM/MeOH (20:1) to afford the tert-butyl4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.37 g, 97%). ¹H NMR (CDCl₃, 400 MHz) δ 8.51 (m, 1H), 5.06-5.04 (m,1H), 3.80-3.69 (m, 4H), 3.56-3.45 (m, 4H), 3.10-3.05 (m, 1H), 2.94-2.86(m, 1H), 2.51-2.44 (m, 1H), 2.00-1.94 (m, 1H), 1.48 (s, 9H). MS (APCI+)[M+H] ⁺321.

Step 8:

To a solution of tert-butyl4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.37 g, 1.2 mmol) in DCM (20 mL) was added HCl in dioxane (4M, 5 mL).The mixture was stirred at room temperature overnight. The solvent wasremoved to afford the4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (0.25 g, 98%). MS (APCI+) [M+H] ⁺221.

Step 9:

To a solution of4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (40 mg, 0.14 mmol) in DCM (20 mL) and TEA (2 mL) wasadded3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid(47 mg, 0.14 mmol) and HBTU (52 mg, 0.14 mmol). The mixture was stirredat room temperature for 1 hour. The solvent was removed and the residuewas subject to chromatography on silica gel, eluted by ethyl acetate toafford the tert-butyl2-(4-chlorophenyl)-3-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate(49 mg, 66%). MS (APCI+) [M+H] ⁺544.

Step 11:

To a solution of tert-butyl2-(4-chlorophenyl)-3-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate(49 mg, 0.09 mmol) in DCM (10 mL) was added HCl in dioxane (4M, 2 mL).The mixture was stirred at room temperature overnight. The solvent wasremoved to afford the2-(4-chlorophenyl)-1-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onedihydrochloride (46 mg, 99%). ¹H NMR (D₂O, 400 MHz) δ 8.38-8.36 (m, 1H),7.37-7.34 (m, 2H), 7.22-7.19 (m, 2H), 5.18-5.10 (m, 1H), 4.34-4.28 (m,1H), 4.10-3.00 (m, 12H), 2.50-2.40 (m, 1H), 1.85-1.75 (m, 1H), 1.28-1.26(m, 6H), 1.20-1.13 (m, 3H). MS (APCI+) [M+H] ⁺444.

Example 13

2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(7-methoxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.39 (s, 1H), 7.40-7.36 (m, 2H), 7.22-7.16 (m,2H), 4.90-4.85 (m, 1H), 4.30-4.28 (m, 1H), 4.12-4.00 (m, 1H), 3.92-3.80(m, 2H), 3.79-3.70 (m, 1H), 3.58-3.18 (m, 7H), 3.15-2.80 (2H), 2.46-2.35(m, 1H), 1.95-1.83 (M, 1H), 1.20-1.14 (m, 6H). MS (APCI+) [M+H] ⁺458.

Example 14

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one

Step 1:

Ethyl pulegenate (130 g, 662 mmol) in EtOAc (900 mL) was cooled to −78°C. using a dry ice-isopropanol bath. This mixture was subjected toozonolysis until the reaction turned purple in color. At this point,ozone generation ceased, and the reaction was removed from the dry-icebath. Oxygen was bubbled through the reaction mixture until it turnedyellow. The reaction mixture was concentrated under vacuum, and theresulting residue was dissolved in glacial acetic acid (400 mL). Thesolution was cooled to 0° C., and Zn dust (65 g, 993 mmol) was addedportionwise over 30 minutes. The reaction was then allowed to stir for 2hours, at which point the reaction mixture was filtered through a pad ofcelite to remove the zinc dust. The acetic acid was neutralized to pH 7with aqueous NaOH and NaHCO₃ and extracted with ether (3×800 mL). Thecombined organics were dried with brine, MgSO₄ and concentrated to give(2R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate as a brown liquid (107g, 95%).

Step 2:

Ammonium acetate (240.03 g, 3113.9 mmol) was added to a solution of(R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (106.0 g, 622.78 mmol)in MeOH (1.2 L). The reaction mixture was stirred at room temperatureunder nitrogen for 20 hours, after which it was complete as judged byTLC and HPLC. The reaction mixture was concentrated to remove MeOH. Theresulting residue was dissolved in DCM, washed twice with H₂O, once withbrine, dried (Na₂SO₄), filtered, and concentrated to give (R)-ethyl2-amino-5-methylcyclopent-1-enecarboxylate (102 g, 97% yield) as anorange oil. LC/MS (APCI+) m/z 170 [M+H]+.

Step 3:

A solution containing (R)-ethyl2-amino-5-methylcyclopent-1-enecarboxylate (161.61 g, 955.024 mmol) andammonium formate (90.3298 g, 1432.54 mmol) in formamide (303.456 ml,7640.19 mmol) was heated to an internal temperature of 150° C. andstirred for 17 hours. The reaction mixture was cooled, and transferredto a 2 L single neck flask. Then excess formamidine was removed by highvacuum distillation. Once formamidine stopped coming over, the remainingoil in the still pot was dissolved in DCM and washed with brine (3×200mL). The combined aqueous washes were extracted with DCM. The combinedorganic extracts were dried (Na₂SO₄), filtered, and concentrated. Theresulting brown oil was dissolved in minimal DCM, and this solution wasadded using a separatory funnel to a stirred solution of ether (ca. 5vol of ether vs. DCM solution), causing some brown precipitate to form.This brown precipitate was removed by filtration through a medium fritfunnel which was rinsed with ether and disposed. The filtrate wasconcentrated, the trituration from ether repeated two more times andthen dried on high vacuum line to give(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (93.225 g,65.00% yield) as a brown-yellow pasty solid. LC/MS (APCI−) m/z 149.2.

Step 4:

Neat POCl₃ (463.9 ml, 5067 mmol) was added slowly by addition funnel toa 0° C. solution of(R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (152.2 g, 1013mmol) in DCE (1.2 L). After the addition was complete, the reactionmixture was warmed to room temperature, then heated to reflux andstirred for 70 minutes. The reaction was complete as determined by HPLC.The reaction mixture was cooled to room temperature, and the excessPOCl₃ was quenched in 4 portions as follows: Reaction mixturetransferred to separatory funnel and dripped into a beaker containingice and saturated NaHCO₃ solution cooled in an ice bath. Once theaddition of each portion of the reaction mixture was completed, thequenched mixture was stirred 30 minutes to ensure complete destructionof POCl₃ prior to transfer to separatory funnel. The mixture wastransferred to the separatory funnel and extracted twice with DCM. Thecombined extracts were dried (Na₂SO₄), filtered, and concentrated. Thecrude was purified on silica gel as follows: silica gel (1 kg) wasslurried in 9:1 hexane:ethyl acetate onto a 3 L fritted funnel, silicasettled under vacuum, topped with sand. The crude was loaded with aDCM/hexane mixture, and the compound was eluted using 1 L sidearm flasksunder vacuum. High Rf byproducts eluted first, then(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (104.4 g,61.09% yield) as a brown oil. Triethylamine (93.0 ml, 534 mmol) andtert-butyl piperazine-1-carboxylate (34.8 g, 187 mmol) was added to asolution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine(30.0 g, 178 mmol) in n-BuOH (250 mL). The reaction mixture was heatedto reflux under nitrogen and stirred overnight (17 hours), after whichit was concentrated on a rotavap. The resulting oil was dissolved inDCM, washed with H₂O, dried (Na₂SO₄), filtered, and was concentrated.The resulting brown oil was purified on silica gel eluting first with2:1 hexanes:ethyl acetate until product eluting cleanly, then gradient1:1 to 1:5 DCM:ethyl acetate to give (R)-tertbutyl4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(42.0 g, 74.1% yield) as a beige powder. LC/MS (APCI+) m/z 319.1 [M+H]⁺.

Step 5:

Solid 77% max. MCPBA (23.9 g, 107 mmol) was added portionwise to a 0° C.solution of (R)-tert-butyl4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(20.0 g, 62.8 mmol) in CHCl₃ (310 mL). The reaction mixture was stirred5 for minutes, then warmed to room temperature and stirred for 90minutes. HPLC looked similar after 7.5 hours. The reaction mixture wascooled to 0° C., then NaHCO₃ (13.2 g, 157 mmol) and another 0.5equivalents of m-CPBA were added. The reaction mixture was stirredovernight (14 hours). The reaction mixture was cooled to 0° C., and asolution of Na₂S₂O₃ (29.8 g, 188 mmol) in H₂O (50 mL) was added dropwiseby addition funnel. This was followed by a solution of Na₂CO₃ (24.6 g,232 mmol) in H₂O (70 mL) by addition funnel (mixture turns homogeneous).The reaction mixture was stirred for 30 minutes, then the mixture wasextracted with CHCl₃ (3×150 mL). The combined extracts were dried(Na₂SO₄), filtered, and concentrated to give the N-oxide. LC/MS (APCI+)m/z 335.1 [M+H]+.

Step 6:

Ac₂O (77.0 ml, 816 mmol) was added to the N-oxide (21.0 g, 62.8 mmol)from Step 5. The reaction mixture was heated under nitrogen in a 90° C.sand bath and stirred for 100 minutes. The reaction mixture was cooledto room temperature, and excess acetic anhydride was removed by rotaryevaporation. The resulting oil was dissolved in DCM, which was thenpoured carefully into ice saturated Na₂CO₃. The mixture was extractedwith DCM, and the combined extracts were dried (Na₂SO₄), filtered, andconcentrated to give (5R)-tert-butyl4-(7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(23.6 g, 100%) as a brown foam. LC/MS (APCI+) m/z 377.1 [M+H]+.

Step 7:

LiOH—H₂O (6.577 g, 156.7 mmol) was added to a 0° C. solution of(5R)-tert-butyl4-(7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(23.6 g, 62.69 mmol) in 2:1 THF:H₂O (320 mL). The reaction mixture wasstirred for 10 minutes, and then warmed to room temperature. LC/MSlooked the same at 3 hours and 4.5 hours. The reaction mixture wascooled to 0° C., and then saturated NH₄Cl was added to the mixture. Themixture was stirred for 5 minutes, and most of the THF was removed byrotary evaporation. The mixture was extracted with EtOAc (3×250 mL), andthe combined extracts were dried (Na₂SO₄), filtered, and concentrated.The crude was flashed on Biotage 65M: 4:1 DCM:ethyl acetate, thengradient to 1:1 to 1:4 DCM:ethyl acetate. Once the product was eluting,then ethyl acetate was flushed through the column. Then 30:1 DCM:MeOHeluted the rest of the product (8.83 g). The mixed fractions werere-flashed with Biotage 40M using the same conditions to give another2.99 g which gave a combined yield of (5R)-tert-butyl4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(11.82 g, 56.38% yield) as a brown foam. LC/MS (APCI+) m/z 335.1 [M+H]+.

Step 8:

A solution of DMSO (5.45 ml, 76.8 mmol) in DCM (50 mL) was addeddropwise by addition funnel to a −78° C. solution of oxalyl chloride(3.35 ml, 38.4 mmol) in DCM (150 mL). The reaction mixture was stirredfor 35 minutes, and then a solution of (5R)-tert-butyl4-(7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(9.17 g, 27.4 mmol) in DCM (80 mL) was added slowly by addition funnel.The reaction mixture was stirred another 1 hour at −78° C., after whichneat triethylamine (18.0 ml, 129 mmol) was added to the mixture. Thereaction mixture was then allowed to warm to room temperature, and thenit was stirred for 30 minutes. H₂O was added. The mixture was extractedwith DCM (3×200 mL), and the combined extracts were dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude was purified on silicagel (Biotage 65M): the column was flushed with ca. 800 mL 4:1 DCM:EtOAc,then gradient to 1:1 DCM:ethyl acetate until product eluting, then 1:4DCM:EtOAc eluted product to give (R)-tert-butyl4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(7.5 g, 82.3% yield) as a brown foam. The foam was concentrated (3×)from DCM/hexanes, which gave a very light brown foam. HPLC >95% area.LC/MS (APCI+) m/z 333 [M+H]+.

Step 9:

Triethylamine (4.33 ml, 31.1 mmol; degassed with nitrogen 30 minutesprior to use) and formic acid (1.36 ml, 36.1 mmol; degassed withnitrogen 30 minutes prior to use) were added to a solution of(R)-tert-butyl4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(9.75 g, 29.3 mmol) in DCM (210 mL; degassed with nitrogen 30 minutesprior to use). The mixture was stirred for 5 minutes, then a Ru catalyst(0.0933 g, 0.147 mmol) was added. The reaction was stirred underpositive nitrogen pressure overnight (18 hours). The reaction mixturewas concentrated to dryness and dried on high vacuum. The impurematerial was flashed on Biotage 65M loaded 1:1 DCM:ethyl acetate 500 mLflushed, then 1:4 DCM:ethyl acetate until product (2nd spot), thengradient to neat ethyl acetate, then 25:1 DCM:MeOH eluted rest ofproduct. The fractions were combined and concentrated on a rotaryevaporator. The residue was concentrated again from DCM/hexanes to givea mixture of tert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(major) and tert-butyl4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(minor) (9.35 g, 95.3% yield) as a beige foam. LC/MS (APCI+) m/z 335[M+H]+. 1H NMR (CDCl3) shows 88% de by integration of carbinol methine.

Step 10:

4-Nitrobenzoyl chloride (4.27 g, 23.0 mmol) was added to a 0° C.solution of tert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(7.0 g, 20.9 mmol) and triethylamine (4.38 ml, 31.4 mmol) in DCM (110mL). The reaction mixture was stirred at room temperature overnight,after which saturated NaHCO₃ was added. The mixture was stirred 10minutes, and then extracted with DCM. The combined extracts were dried(Na₂SO₄), filtered, and concentrated. The crude was flashed on Biotage65M (3:1 hexanes:ethyl acetate loaded crude, then 2:1 hexanes:ethylacetate eluted tert-butyl4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylateand a few mixed fractions). Then tert-butyl4-((5R,7S)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylatewas eluted using 1:2 hexanes:ethyl acetate. The fractions with productwere concentrated by rotary evaporation to give tert-butyl4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(8.55 g, 84.5% yield) as a yellow foam. LC/MS (APCI+) m/z 484 [M+H]+. 1HNMR (CDCl3) shows single diastereomer). The fractions with otherdiastereomer were concentrated by rotary evaporation to give tert-butyl4-((5R,7S)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.356 g, 3.52% yield) as a brown foam. LC/MS (APCI+) m/z 484 [M+H]+.

Step 11:

LiOH—H₂O (0.499 g, 11.9 mmol) was added to a 0° C. solution oftert-butyl4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(2.30 g, 4.76 mmol) in 2:1 THF:H₂O (40 mL). The reaction mixture waswarmed to room temperature and stirred for 1 hour. The THF was removedby rotary evaporation, saturated NaHCO₃ was added, and the mixture wasextracted with ethyl acetate. The combined extracts were washed (1×)with saturated NaHCO₃, dried (Na₂SO₄), filtered, and concentrated togive tert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(1.59 g, 100.0% yield) as a yellow foam. HPLC after workup justproduct >98 area % pure. LC/MS (APCI+) m/z 335 [M+H]+. The tert-butyl4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylatewas prepared using an analogous method.

Step 12

4M HCl/dioxane (11.2 ml, 44.9 mmol) was added to a solution oftert-butyl4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(0.600 g, 1.79 mmol) in dioxane (15 mL). The reaction mixture wasstirred at room temperature under nitrogen overnight (20 hours). Themixture was concentrated to dryness and dried on high vacuum line. Thecrude was suspended in ether, sonicated, and stirred for 5 minutes. Thesolids were isolated by filtration through a medium frit funnel withnitrogen pressure, rinsed with ether, dried under nitrogen pressure, anddried further on a hi vacuum line to give(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (0.440 g, 79.8% yield) as a yellow powder. LC/MS (APCI+)m/z 235. The(5R,7S)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride was prepared using an analogous method.

Step 13:

Methyl 2-(4-chlorophenyl)acetate (36.7 g, 199 mmol) and paraformaldehyde(6.27 g, 209 mmol) were dissolved/suspended in DMSO (400 mL) and treatedwith NaOMe (537 mg, 9.94 mmol). The mixture was allowed to stir at roomtemperature for 2 hours to completion by TLC analysis of the crude. Thereaction was poured into ice-cold water (700 mL; white emulsion) andneutralized with the addition of 1M HCl solution. The aqueous layer wasextracted with ethyl acetate (3×), and the organics were combined. Theorganic layer was washed with water (2×), brine (1×), separated, driedover MgSO₄, filtered, and concentrated in vacuo to afford the crudeproduct as a yellow oil. The residue was loaded onto a large frittedfiltered with silica gel and eluted with 9:1 hexanes:ethyl acetate untilthe starting material/olefin were collected. The plug was then elutedwith 1:1 hexanes:ethyl acetate until the pure desired product was elutedcompletely. The concentrated pure fractions yielded methyl2-(4-chlorophenyl)-3-hydroxypropanoate as a colorless oil (39.4 g, 92%).

Step 14:

Methyl 2-(4-chlorophenyl)-3-hydroxypropanoate (39.4 g, 184 mmol) wasdissolved in DCM (500 mL) and treated with TEA (64.0 mL, 459 mmol). Thesolution was cooled to 0° C. and slowly treated with MsCl (15.6 mL, 202mmol), then allowed to stir for 30 minutes to completion by TLCanalysis. The solution was partitioned with 1N HCl solution, and theaqueous layer was extracted once with DCM. The combined organic layerwas washed once more with 1N HCl solution, separated, washed withdiluted NaHCO₃ solution, and separated. The organic layer was dried overMgSO₄, filtered, and concentrated in vacuo to afford an orange oil. Theresidue was loaded onto a large fritted filter with a plug of silica geland eluted with 9:1 hexanes:ethyl acetate affording the pure desiredproduct by TLC analysis. The concentrated pure fractions yielded themethyl 2-(4-chlorophenyl)acrylate as a colorless oil (30.8 g, 85%). Thismethyl 2-(4-chlorophenyl)acrylate (500 mg, 2.54 mmol) was added as asolution in THF (1.35 mL) to a stirring solution of i-PrNH₂ (217 uL,2.54 mmol) in THF (5.0 mL) at 0° C. The reaction was allowed to stir atroom temperature overnight to completion by LCMS analysis. The Boc2O(584 uL, 2.54 mmol) was added to the stirring amine via pipet. Thereaction was allowed to stir overnight to completion by LCMS and TLCanalysis of the mixture. The solution was concentrated in vacuo toafford methyl3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate asa colorless oil (854 mg, 94%). LC/MS (APCI+) m/z 256.1 [M−Boc]+.

Step 15:

Methyl3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate(133 g, 374 mmol) was dissolved in THF (1.0 L) and treated with KOTMS(56.0 g, 392 mmol) at room temperature. The mixture was allowed to stirovernight to completion by LCMS analysis of the crude. The mixture wasconcentrated in vacuo to afford a wet foam, which was allowed to dryunder vacuum overnight to afford potassium3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate asa white solid (148.7 g, 105%). LC/MS (APCI+) m/z 242.1 [M−Boc−K]+.

Step 16:

Potassium3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate(77.2 g, 203 mmol) was dissolved in THF (515 mL) and treated withpivaloyl chloride (26.3 mL, 213 mmol) at room temperature. The mixturewas allowed to stir for 3 hours to form the mixed anhydride.(S)-4-benzyloxazolidin-2-one (46.1 g, 260 mmol) was dissolved in THF(600 mL) and cooled to −78° C. in a separate flask. The solution wastreated with n-BuLi (102 mL of a 2.50M solution in hexanes, 254 mmol)and allowed to stir for one hour. The prepared anhydride solution wasadded to the stirring Li-oxazolidinone via cannula, and the mixture wasallowed to warm to room temperature overnight. The mixture was quenchedwith the addition of saturated ammonium chloride solution, thenpartitioned between more water and ethyl acetate. The aqueous layer wasextracted several times, and the organics were combined. The organiclayer was washed with water, then brine, separated, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified/separated(diastereomers) via chromatography (silica gel eluted with 4:1hexanes:ethyl acetate) to afford the completely separated diastereomersas viscous oils: tert-butyl(R)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate(12.16 g, 24% based on ½ of acid racemate) and tert-butyl(S)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate(39.14 g, 77% based on ½ of acid racemate). LC/MS (APCI+) m/z 401.2[M−Boc]+.

Step 17:

LiOH—H₂O (168 mg, 4.00 mmol) was added to a stirring solution of THF (30mL) and water (15 mL) at room temperature until it was dissolved. Themixture was treated with hydrogen peroxide (658 uL of a 35% wt. solutionin water, 8.00 mmol) and allowed to stir at room temperature for 10minutes. The reaction was cooled to 0° C. in an ice bath, and thetert-butyl(S)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate(1.00 g, 2.00 mmol) was added dropwise via addition funnel as a solutionin THF (15 mL) over a 10 minutes. The mixture was allowed to stirovernight at room temperature to completion by LCMS analysis of thecrude. The reaction was cooled to 0° C., and then treated with 1M Na₂SO₃(9.00 mL) solution via addition funnel over a ten minute period. Afterthe addition was complete, the mixture was allowed to warm to roomtemperature for 10 minutes. The mixture was concentrated to remove theTHF, and then diluted with water. The aqueous layer was washed twicewith ethyl acetate (discarded). The aqueous layer was partitioned withethyl acetate, then treated dropwise while stirring with 1M HCl until pH2-3 was attained. The aqueous layer was extracted twice with ethylacetate, and the organics were combined. The organic was washed withbrine, separated, dried over MgSO₄, filtered, and concentrated in vacuo.The colorless oil product was dried under high vacuum for one hour toafford(S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoicacid as a viscous oil/foam (685 mg, 100%). LC/MS (APCI+) m/z 242.1[M−Boc]+.

Step 18:

A solution of(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (2.92 g, 9.51 mmol) and(S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoicacid (3.25 g, 9.51 mmol) in DCM (40 mL) and DIEA (5.0 mL, 28.7 mmol) wasstirred at room temperature for 10 minutes. HBTU (3.61 g, 9.51 mmol) wasadded to the mixture. The mixture was stirred at room temperature for 1hour. The solvent was removed, and the residue was dissolved in ethylacetate (500 mL) and washed with water (6×100 mL). The organic phase wasdried and concentrated. The residue was subject to columnchromatography, eluted by EtOAc-DCM/MeOH (20:1) to give tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate(3.68 g, 69%.) LC/MS (APCI+) m/z 558.2 [M+H]+.

Step 19:

The tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate(2.50 g, 4.48 mmol) was dissolved in dioxane (22.4 mL) and treated with4M HCl in dioxane (22.4 mL, 89.6 mmol) at room temperature. Theresulting solution was allowed to stir overnight to completion by LCMSanalysis of the crude. The solution was concentrated in vacuo to afforda gel that was dissolved in a minimal amount of methanol (10 mL). Thesolution was transferred via pipette to stirred ether (300 mL) to afforda white precipitate of desired product. The addition was about half whenthe white precipitate melted into a yellow gel. The material wasconcentrated in vacuo to afford a yellow gel which was allowed to standunder reduced pressure overnight to yield(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onedihydrochloride as a light yellow powder (2.14 g, 90%).

¹H NMR (D₂O, 400 MHz) δ 8.39 (s, 1H), 7.37-7.35 (d, J=8.4 Hz, 2H),7.23-7.20 (d, J=8.4 Hz, 2H), 5.29-5.25 (m, 1H), 4.33-4.29 (m, 1H),4.14-4.10 (m, 1H), 3.89-3.19 (m, 11H), 2.23-2.17 (m, 1H), 2.08-1.99 (m,1H), 1.20-1.18 (m, 6H), 0.98-0.96 (d, J=6.8 Hz, 3H). MS (APCI+) [M+H]⁺458.

Example 15

2-(4-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.39 (m, 1H), 7.27-7.25 (m, 2H), 7.11-7.07 (m,2H), 5.29-5.25 (m, 1H), 4.33-4.30 (m, 1H), 4.20-3.00 (m, 12H), 2.22-2.18(m, 1H), 2.06-2.00 (m, 1H), 1.20-1.10 (m, 6H), 1.08-0.96 (m, 3H). MS(APCI+) [M+H] ⁺442.

Example 16

2-(3,4-difluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.37-8.25 (m, 1H), 7.36-7.16 (m, 9H), 5.37-5.22(m, 1H), 4.33-4.30 (m, 1H), 4.25-3.00 (m, 13H), 2.22-2.18 (m, 1H),2.06-1.98 (m, 1H), 1.29-1.22 (m, 3H), 1.20-0.96 (m, 3H). MS (APCI+)[M+H] ⁺550.

Example 17

2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(pyridin-3-ylmethylamino)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.84 (m, 1H), 8.75 (m, 1H), 8.68-8.54 (m, 1H),8.39 (m, 1H), 8.03-8.01 (m, 1H), 7.36-7.33 (m, 2H), 7.22-7.19 (m, 2H),5.28-5.22 (m, 1H), 4.50-4.40 (m, 1H), 4.20-3.05 (m, 12H), 2.21-2.15 (m,1H), 1.20-1.10 (m, 2H), 1.08-0.95 (m, 3H). MS (APCI+) [M+H] ⁺507.

Example 18

2-(2,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.41-8.38 (m, 1H), 7.58 (s, 1H), 7.40-7.26 (m,1H), 7.12-7.10 (m, 1H), 5.36-5.27 (m, 1H), 4.18-3.10 (m, 13H), 2.23-2.18(m, 1H), 2.08-2.00 (m, 1H), 1.30-1.20 (m, 6H), 1.08-0.98 (m, 3H). MS(APCI+) [M+H] ⁺492.

Example 19

2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(pentan-3-ylamino)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.39-8.37 (d, J=7.2 Hz, 1H), 7.36-7.34 (m, 2H),7.22-7.20 (d, J=8.4 Hz, 2H), 5.30-5.25 (m, 1H), 4.33-4.29 (m, 1H),4.18-3.00 (m, 12H), 2.24-2.15 (m, 4H), 2.10-2.00 (m, 1H), 1.30-1.20 (m,4H), 1.12-0.95 (m, 3H), 0.90-0.86 (m, 6H). MS (APCI+) [M+H] ⁺486.

Example 20

2-(4-chlorophenyl)-3-((1S,2R)-1-hydroxy-1-phenylpropan-2-ylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.39 (m, 1H), 7.27-7.16 (m, 2H), 7.06-7.04 (m,1H), 5.25-5.22 (m, 1H), 4.33-4.30 (m, 1H), 4.25-3.00 (m, 14H), 2.22-2.18(m, 1H), 2.06-1.98 (m, 1H), 1.20-1.10 (m, 6H), 1.08-0.96 (m, 3H). MS(APCI+) [M+H] ⁺460.

Example 21

2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((1R,4R)-4-hydroxycyclohexylamino)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.30 (m, 1H), 7.38-7.33 (m, 2H), 7.22-7.19 (m,2H), 5.30-5.20 (m, 1H), 4.40-4.33 (m, 1H), 4.20-3.05 (m, 12H), 2.21-2.15(m, 1H), 1.80-1.10 (m, 9H), 1.08-0.95 (m, 3H). MS (APCI+) [M+H] ⁺514.

Example 22

((3S,4R)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanoneand((3R,4S)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone

Step 1:

TFA (0.2 mL, 2.63 mmol) was added to a solution of (E)-methyl3-(3,4-dichlorophenyl)acrylate (2.6 g, 11.7 mmol) in DCM (40 mL). Themixture was cooled to 0° C. Then benzylmethoxytrimethylsilanylmethylamine (6.0 mL, 23.5 mmol) was added dropwisely while maintainingthe temperature between −5° C. and +5° C. After the addition wascomplete, the mixture was stirred at room temperature overnight. Thesolvent was removed, and the residue was dissolved in ether and treatedwith 1N HCl. The mixture was shaken to agitate, and a three layersolution formed. The lower two layers were collected and basified with2N NaOH to a pH of 14, extracted with CHCl₃ (3×100 mL). The organicphase was dried, filtered and concentrated. The residue was subjected tocolumn chromatography, eluted by hexane/ethyl acetate (4:1) to give(3S,4R)-methyl 1-benzyl-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate(4.2 g, 99%.) (LCMS (APCI+) [M+H]⁺ 364.2; Rt: 2.63 min.)

Step 2:

1-Chloroethyl chloroformate (1.5 mL, 13.9 mmol) was added to a solutionof (3S,4R)-methyl1-benzyl-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate (4.20 g, 11.5mmol) in DCE (50 mL) at 0° C. The mixture was refluxed for 1 hour. Aftercooling, the solvent was removed under vacuum at 65° C. for 1 hour. MeOH(50 mL) was added to the residue and refluxed for 1 hour. The MeOH wasremoved. The solid was redissolved in CHCl₃ and treated with saturatedNa₂CO₃. The aqueous layer was separated and extracted with CHCl₃ (2×30mL). The organic phase was combined and dried. The solvent was removedto afford (3S,4R)-methyl 4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate(3.1 g, 98%). (LCMS (APCI+) [M+H]⁺ 274.1; Rt: 2.25 min.).

Step 3:

Boc anhydride (3.0 g, 13.7 mmol) was added to a solution of(3S,4R)-methyl 4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate (3.10 g,11.3 mmol) in THF (100 mL) and TEA (4 mL). The mixture was stirred atroom temperature overnight. The solvent was removed, and the residue wassubject to column chromatography, eluted by hexane/ethyl acetate (8:1)to give (3S,4R)-1-tert-butyl 3-methyl4-(3,4-dichlorophenyl)pyrrolidine-1,3-dicarboxylate (LCMS (APCI+)[M−Boc+H]⁺ 274.1; Rt: 4.17 min). The (3S,4R)-1-tert-butyl 3-methyl4-(3,4-dichlorophenyl)pyrrolidine-1,3-dicarboxylate was redissolved inMeOH (50 mL), and LiOH (3M, 10 mL) was added. The mixture was stirred atroom temperature for 6 hours. 2N HCl (15 mL) was added to the mixture.The solvent was removed, and the residue was subject to columnchromatography, eluted by DCM/MeOH (40:1-10:1) to give(3S,4R)-1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylicacid (1.95 g). (LCMS (APCI+) [M−Boc+H]⁺ 260.1; Rt: 3.67 min.)

Step 4:

HBTU (37 mg, 0.098 mmol) was added to a solution of(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (30 mg, 0.098 mmol) and1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylicacid (35 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture wasstirred at room temperature for 1 hour. The solvent was removed, and theresidue was dissolved in ethyl acetate (50 mL) and washed with brine(5×50 mL). The organic phase was dried and concentrated to affordtert-butyl3-(3,4-dichlorophenyl)-4-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate(LCMS (APCI+) [M+H]+ 576.1; Rt: 2.90 min). The product was treated with4N HCl in dioxane to afford(4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanoneas the HCl salt (30 mg, 64%).

Obtained as a 1:1 mixture of diastereomers. ¹H NMR (D₂O, 400 MHz) δ8.44-8.10 (m, 1H), 7.48-7.40 (m, 2H), 7.24-7.12 (m, 1H), 5.33-5.28 (m,1H), 4.00-3.85 (m, 1H), 3.80-3.00 (m, 11H), 2.26-2.20 (m, 1H), 2.10-2.00(m, 1H), 1.08-1.00 (m, 3H). MS (APCI+) [M+H] ⁺476.

Example 23

2-(4-chlorophenyl)-2-hydroxy-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one

Step 1:

MCPBA (35 g, 77%, 156 mmol) was added to a solution of methyl2-(4-chlorophenyl)-acrylate (20 g, 102 mmol) in CHCl₃ (200 mL). Themixture was refluxed for 24 hours. The reaction was cooled to roomtemperature, diluted with chloroform (200 mL) and washed with 10%Na₂S₂O₃, 10% NaHCO₃ and water. The organic phase was dried andconcentrated. The residue was subject to column chromatography, elutedby hexane/ethyl acetate (9:1) to give methyl2-(4-chlorophenyl)oxirane-2-carboxylate. Methyl2-(4-chlorophenyl)oxirane-2-carboxylate (2 g, 9.4 mmol) and ethanol (10mL) and isopropylamine (1 mL, 11.7 mmol) were added to a 50 mL highpressure bomb. The mixture was heated to 90° C. for 12 hours in thebomb. After cooling, the solvent was removed, and the residue wasdissolved in DCM (20 mL) and TEA (2 mL). (Boc)2O (4 g, 23.0 mmol) wasadded to it. The mixture was stirred at room temperature for 48 hours.The solvent was removed, and the residue was dissolved in THF (20 mL).LiOH (3M, 14 mL) was added to the mixture. The mixture was stirred atroom temperature for 16 hours and refluxed for 2 hours. After cooling,the mixture was quenched with 2N HCl (21 mL). The solvent was removedand the residue was subject to column chromatography, eluted byhexane/ethyl acetate (1:1) to give3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-2-hydroxypropanoicacid. LCMS (APCI+) [M−Boc+H]⁺ 258.1; Rf: 3.66 min.

Step 2:

HBTU (37 mg, 0.098 mmol) was added to a solution of(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (30 mg, 0.098 mmol) and3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-2-hydroxypropanoicacid (35 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture wasstirred at room temperature for 1 hour. The solvent was removed, and theresidue was subject to column chromatography, eluted by DCM/MeOH (40:1).The resulting product was treated with HCl (4M, 2 mL) to afford2-(4-chlorophenyl)-2-hydroxy-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-oneas HCl salt (22 mg, 48%).

¹H NMR (D₂O, 400 MHz) δ 8.35-8.34 (m, 1H), 7.41-7.36 (m, 4H), 5.26-5.18(m, 1H), 4.18-3.00 (m, 12H), 2.20-2.14 (m, 1H), 2.08-1.98 (m, 1H),1.20-1.10 (m, 6H), 1.08-0.98 (m, 3H). MS (APCI+) [M+H] ⁺474.

Example 24

4-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

Step 1:

1,8-Diazabicyclo[5.4.0]undec-7-ene (33.68 mL, 225.2 mmol) was added to asolution of methyl 2-(4-chlorophenyl)acrylate (36.9 g, 187.7 mmol) and2-nitropropane (20.23 mL, 225.2 mmol) in CH₃CN (500 mL) at 0° C. undernitrogen. The mixture was warmed to room temperature and stirredovernight. The solution was concentrated in vacuo and subjected tocolumn chromatography (20% EtOAc/hexanes) to give methyl2-(4-chlorophenyl)-4-methyl-4-nitropentanoate (52.9 g, 98.66% yield) asa colourless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.31-7.29 (m, 2H), 7.21-7.19(m, 2H), 3.66 (s, 3H), 3.60-3.57 (m, 1H), 2.87-2.81 (dd, 1H), 2.39-2.34(dd, 1H), 1.56 (s, 3H), 1.55 (s, 3H).

Step 2:

Zn dust (128 g, 1.960 mol) was treated with a solution of methyl2-(4-chlorophenyl)-4-methyl-4-nitropentanoate (28 g, 98.0 mmol)dissolved in ethanol (490 mL). Concentrated HCl (26.9 mL, 323 mmol) wasadded slowly, and then the reaction was heated to 70° C. for 2 hours.The reaction mixture was filtered through a plug of SiO₂ and celite. Thefilter pad was washed with ethyl acetate, and the filtrate wasconcentrated in vacuo. The residue was dissolved in a minimum amount ofethanol and then treated with water.3-(4-Chlorophenyl)-5,5-dimethylpyrrolidin-2-one precipitated from thesolution and was collected by filtration. The solid was washed withwater and air-dried, (11.2 g, 51% yield). ¹H NMR (CD₃OD, 400 MHz) δ7.35-7.32 (m, 2H), 7.26-7.24 (m, 2H), 3.94-3.90 (m, 1H), 2.50-2.44 (m,1H), 1.99-1.93 (m, 1H), 1.36 (s, 3H), 1.34 (s, 3H).

Step 3:

Lithium bis(trimethylsilyl)amide (36 mL, 36 mmol) was added to a stirredsolution of 3-(4-chlorophenyl)-5,5-dimethylpyrrolidin-2-one (6.7 g, 30mmol) in THF (200 mL) at −78° C. under nitrogen. The solution wasstirred at −78° C. for 30 minutes. Then a solution of di-tert-butyldicarbonate (7.6 mL, 33 mmol) in THF (30 mL) was added in a singleportion. The solution was warmed to room temperature and allowed to stirat room temperature overnight. The reaction was poured into 0.5M HClsolution and extracted with ethyl acetate twice. The combined organiclayer was washed with water, separated, dried over MgSO₄, filtered, andconcentrated in vacuo to afford the near-pure product (excess Boc2O) asa colorless oil. Column chromatography (20% EtOAc/hexanes) to give puretert-butyl4-(4-chlorophenyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate. LCMS(APCI+) [M−Boc+H]+ 224.1; Rt: 3.68 min. ¹H NMR (CDCl₃, 400 MHz) δ7.32-7.30 (m, 2H), 7.22-7.20 (m, 2H), 3.80-3.74 (m, 1H), 2.33-2.28 (m,1H), 2.05-1.97 (m, 1H), 1.58 (s, 3H), 1.55 (s, 9H), 1.53 (s, 3H).

Step 4:

Lithium hydroxide hydrate (6.44 mL, 232 mmol) was added to a stirredsolution of tert-butyl4-(4-chlorophenyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (7.5 g,23.2 mmol) in THF/MeOH/H₂O (30 mL/30 mL/30 mL) at room temperature. Themixture was stirred at room temperature overnight and concentrated invacuo. The mixture was taken up into water (200 mL), washed with EtOAc(100 mL), acidified with concentrated HCl and extracted into EtOAc(2×200 mL). The mixture was dried over Na₂SO₄ and concentrated in vacuo.Residual HCl was removed by evaporating from toluene to give4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-4-methylpentanoic acid(5.0 g, 63.2% yield) as a white solid. LCMS (APCI⁺) [M−Boc+H]⁺ 242.0;Rt: 2.8 min.

Step 5:

HBTU (37 mg, 0.098 mmol) was added to a solution of(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (30 mg, 0.098 mmol) and4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-4-methylpentanoic acid(33 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture wasstirred at room temperature for 1 hour. The solvent was removed, and theresidue was dissolved in ethyl acetate (50 mL) and washed with brine(5×50 mL). The organic phase was dried and concentrated to afford theproduct. The product was treated with HCl to afford4-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-methylpentan-1-oneas HCl salt (22 mg, 49%).

¹H NMR (D₂O, 400 MHz) δ 8.40-8.37 (m, 1H), 7.32-7.29 (m, 2H), 7.25-7.19(m, 2H), 5.29-5.25 (m, 1H), 4.12-4.09 (m, 1H), 4.06-3.18 (m, 9H),2.58-2.48 (m, 1H), 2.24-1.98 (m, 1H), 2.08-2.00 (m, 1H), 1.90-1.80 (m,1H), 1.26-1.09 (m, 6H), 1.08-0.98 (m, 3H). MS (APCI+) [M+H] ⁺458.

Example 25

4-amino-2-(3,4-difluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.40 (m, 1H), 7.32-7.29 (m, 2H), 7.06-7.00 (m,1H), 5.29-5.25 (m, 1H), 4.19-3.22 (m, 10H), 2.58-2.48 (m, 1H), 2.24-1.98(m, 1H), 2.08-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.26-1.09 (m, 6H),1.08-0.98 (m, 3H). MS (APCI+) [M+H] ⁺460.

Example 26

(4-(4-chloro-3-fluorophenyl)piperidin-4-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone

Step 1:

KCN (1.25 g, 19.2 mmol) was added to a solution of4-(bromomethyl)-1-chloro-2-fluorobenzene (3.90 g, 17.5 mmol) in DMSO (60mL). Several milliliters of H₂O were added to help dissolve the KCN.After 1 hour, the reaction mixture was diluted with H₂O and extractedwith EtOAc. The extracts were dried (Na₂SO₄), filtered, andconcentrated. The crude product was flashed on silica (Biotage 40M, 9:1to 4:1 hex:EtOAc) to give 2-(4-chloro-3-fluorophenyl)acetonitrile (1.81g, 61.2% yield) as a yellow crystalline solid.

Step 2:

60% NaH (1.07 g, 26.7 mmol) was added in 2 portions to a 0° C. solutionof 2-(4-chloro-3-fluorophenyl)acetonitrile (1.81 g, 10.7 mmol) and15-crown-5 (0.235 g, 1.07 mmol) in DMF (45 mL). The reaction mixture waswarmed to room temperature and stirred for 35 minutes. The reactionmixture was then cooled to 0° C. NaI (1.60 g, 10.7 mmol) was added, andthen a solution of freshly prepared tert-butylbis(2-chloroethyl)carbamate (2.58 g, 10.7 mmol) in DMF (10 mL) was addedby syringe. The reaction mixture was warmed to room temperature andstirred overnight (19 hours). The reaction mixture was poured into icesaturated NH₄Cl, and the mixture was extracted with EtOAc. The combinedextracts were dried (Na₂SO₄), filtered, and concentrated. The crude wasflashed on silica (Biotage 40 L, 9:1 hex:EtOAc until product eluted,then 6:1 hex:EtOAc to elute product) to give tert-butyl4-(4-chloro-3-fluorophenyl)-4-cyanopiperidine-1-carboxylate (1.96 g,54.2% yield) as a yellow oil. LC/MS (APCI+) m/z 239 [M−Boc+H]+.

Step 3:

Tert-butyl 4-(4-chloro-3-fluorophenyl)-4-cyanopiperidine-1-carboxylate(1.96 g, 5.785 mmol) was dissolved in concentrated HCl (48.21 mL, 578.5mmol), heated to reflux, and then stirred over the weekend(approximately 60 hours). The reaction mixture was cooled to roomtemperature, transferred to a separatory funnel, and washed with ether.The aqueous layer was concentrated on a rotary evaporator and dried on ahigh vacuum line. The resulting solids were dissolved in 10% NaOH (9.255g, 23.14 mmol), dioxane (40 mL) was added, followed by a Boc2O addition(1.326 g, 6.074 mmol). The reaction mixture was stirred at roomtemperature overnight (16 hours). The reaction mixture was then dilutedwith H₂O and washed with ether. The aqueous layer was acidified withsolid KHSO₄, and then extracted with DCM. The combined extracts weredried (Na₂SO₄), filtered, concentrated and dried on a high vacuum lineto give1-(tert-butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidine-4-carboxylicacid (0.910 g, 43.96% yield) as a foam. LC/MS (APCI−) m/z 713 [2M−H]−.

Step 4:

(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (35.0 mg, 0.114 mmol) and1-(tert-butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidine-4-carboxylicacid (40.8 mg, 0.114 mmol) were dissolved in DCM (1.1 mL) and treatedwith DIEA (0.0595 ml, 0.342 mmol) at ambient temperature. The mixturewas allowed to homogenize before the HBTU (47.5 mg, 0.125 mmol) wasadded in one lot. The reaction was allowed to stir for four hours tocompletion by LCMS analysis of the crude. The reaction was diluted withDCM, washed with diluted NaHCO₃ solution, washed with water, washed withbrine, and separated. The organic layer was dried over Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by chromatography(silica gel eluted with 5% methanol in ethyl acetate) to afford the puretert-butyl4-(4-chloro-3-fluorophenyl)-4-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)piperidine-1-carboxylate(15.0 mg, 22.9% yield) as a pale yellow oil. MS (APCI+) [M+H] ⁺574; Rf:2.92.

Step 5:

The tert-butyl4-(4-chloro-3-fluorophenyl)-4-(1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)piperidine-1-carboxylate(15.0 mg, 0.0261 mmol) was dissolved in dioxane (131 uL) and treatedwith 4M HCl (0.131 ml, 0.523 mmol) in dioxane. The mixture was allowedto stir overnight to afford the pure product as a gel precipitate. Thesolvent was removed under reduced pressure, and the foam was trituratedwith ether (sonicated) to afford a white suspension. The ether wasremoved under reduced pressure to afford the pure(4-(4-chloro-3-fluorophenyl)piperidin-4-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanonedihydrochloride (12.0 mg, 84.0% yield) as a white powder. Rf: 1.96.

¹H NMR (D₂O, 400 MHz) δ 8.36 (m, 1H), 7.25-7.00 (m, 3H), 5.28-5.20 (m,1H), 4.00-3.00 (m, 14H), 2.50-2.38 (m, 2H), 2.26-2.00 (m, 2H), 1.04-1.00(m, 3H). MS (APCI+) [M+H] ⁺474.

Example 27

(3-(4-chlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone

Step 1:

TFA (0.34 ml, 4.41 mmol) was added to a solution ofN-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine (3.9 g,19.8 mmol) in DCM (40 mL). The mixture was cooled to 0° C. Thebenzylmethoxytrimethylsilanyl methylamine (10.5 mL, 41 mmol) was addeddropwise at 0° C. The mixture was stirred at room temperature for 2hours. The solvent was removed, and the residue was dissolved in etherand treated with 1N HCl. The mixture was shaken, and the aqueous layerwas separated and basified with 2N NaOH to a pH of 14. The aqueous layerwas extracted with CHCl₃ (3×100 mL). The organic phase was dried andconcentrated. The residue was subjected to column chromatography, elutedby hexanes/ethyl acetate (10:1) to give methyl1-benzyl-3-(4-chlorophenyl)pyrrolidine-3-carboxylate (LCMS (APCI+)[M−Boc+H]⁺ 330.2; Rt: 2.46 min).

Step 2:

1-Chloroethylformate (1.0 mL, 9.27 mmol) was added to a solution ofmethyl 1-benzyl-3-(4-chlorophenyl)pyrrolidine-3-carboxylate (3.05 g,9.25 mmol) in toluene (40 mL) at 0° C. The mixture was refluxed for 10hours. After cooling, the solvent was removed under vacuum. The residuewas treated with MeOH (20 mL) and refluxed for 1 hour. The solvent wasremoved, and the residue was dissolved in ethyl acetate (200 mL). Theresidue was washed with 1N NaOH (50 mL) and then washed with water. Theorganic phase was dried and concentrated. The residue was subjected tocolumn chromatography, eluted by EtOAc-DCM/MeOH (10:1). The resultingmethyl 3-(4-chlorophenyl)pyrrolidine-3-carboxylate (LCMS (APCI+)[M−Boc+H]⁺ 240.1; Rt: 2.06 min) was dissolved in DCM (20 mL) and TEA (1mL). Then is was treated with Boc anhydride (1 g, 4.58 mmol). Afterstirring for 2 hours, the solvent was removed, and the 1-tert-butyl3-methyl 3-(4-chlorophenyl)pyrrolidine-1,3-dicarboxylate (LCMS (APCI+)[M−Boc+H]⁺ 240.1; Rt: 3.78 min) was dissolved in THF (50 mL). LiOH (3M,6 mL) was added to the mixture. The mixture was stirred at roomtemperature overnight. The mixture was quenched with 2N HCl (9 mL). Thesolvent was removed and the residue was subjected to columnchromatography, eluted by Hex/EtOAc (4:1)-DCM/MeOH (20:1) to give1-(tert-butoxycarbonyl)-3-(4-chlorophenyl)pyrrolidine-3-carboxylic acid.LCMS (APCI+) [M−Boc+H]⁺ 224.1; Rt: 2.90 min.

Step 3:

HBTU (37 mg, 0.098 mmol) was added to a solution of(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (30 mg, 0.098 mmol) and1-(tert-butoxycarbonyl)-3-(4-chlorophenyl)pyrrolidine-3-carboxylic acid(32 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture wasstirred at room temperature for 10 hours. The solvent was removed, andthe residue was subjected to column chromatography, eluted by ethylacetate-DCM/MeOH (20:1). The product was treated with HCl (4M, 2 mL) inDCM (5 mL) to afford(3-(4-chlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanoneas the HCl salt (35 mg, 81%).

¹H NMR (D₂O, 400 MHz) δ 8.39-8.37 (d, J=2.8 Hz, 1H), 7.40-7.38 (d, J=8.4Hz, 2H), 7.27-7.25 (d, J=8.4 Hz, 2H), 5.28-5.24 (m, 1H), 4.18-4.10 (m,1H), 4.08-2.98 (m, 12H), 2.83-2.78 (m, 1H), 2.59-2.50 (m, 1H), 2.24-2.15(m, 1H), 2.10-2.00 (m, 1H), 1.20-0.95 (m, 7H). MS (APCI+) [M+H] ⁺442.

Example 28

1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-2-p-tolylpropan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.40-8.39 (m, 1H), 7.20-7.10 (m, 4H), 5.30-5.25(m, 1H), 4.30-4.26 (m, 1H), 4.19-3.00 (m, 12H), 2.24-2.15 (m, 4H),2.10-2.00 (m, 1H), 1.30-1.10 (m, 6H), 1.08-0.95 (m, 3H). MS (APCI+)[M+H] ⁺438.

Example 29

1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-2-(4-methoxyphenyl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.38 (m, 1H), 7.18-7.16 (m, 2H), 6.95-6.92 (d,J=8.8 Hz, 2H), 5.29-5.25 (m, 1H), 4.29-4.25 (m, 1H), 4.20-3.00 (m, 15H),2.23-2.17 (m, 1H), 2.07-1.98 (m, 1H), 1.30-0.95 (m, 9H). MS (APCI+)[M+H] ⁺454.

Example 30

3-(ethylamino)-2-(4-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.39 (m, 1H), 7.28-7.25 (m, 2H), 7.10-7.07 (m,2H), 5.28-5.25 (m, 1H), 4.39-4.37 (m, 1H), 4.20-2.95 (m, 13H), 2.22-2.18(m, 1H), 2.06-1.98 (m, 1H), 1.22-1.14 (m, 3H), 1.04-0.96 (m, 3H). MS(APCI+) [M+H] ⁺428.

Example 31

2-(4-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methylamino)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.40 (m, 1H), 7.28-7.24 (m, 2H), 7.12-7.08 (m,2H), 5.29-5.25 (m, 1H), 4.39-4.37 (m, 1H), 4.20-3.00 (m, 11H), 2.62 (s,3H), 2.22-2.18 (m, 1H), 2.06-1.98 (m, 1H), 1.17-1.14 (m, 1H), 1.04-0.96(m, 3H). MS (APCI+) [M+H] ⁺414.

Example 32

(S)-3-amino-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.40-8.39 (d, J=5.2 Hz, 1H), 7.50-7.43 (m, 2H),7.19-7.16 (d, J=8.0 Hz, 2H), 5.30-5.25 (m, 1H), 4.32-4.29 (m, 1H),4.15-3.00 (m, 11H), 2.26-2.20 (m, 1H), 2.10-2.00 (m, 1H), 1.30-0.98 (m,3H), MS (APCI+) [M+H] ⁺450.

Example 33

2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.16-8.14 (d, J=7.6 Hz, 1H), 7.18-7.16 (m, 2H),7.02-7.00 (d, J=8.0 Hz, 2H), 5.02-4.95 (m, 1H), 4.14-4.10 (m, 1H),3.98-3.00 (m, 11H), 2.89-2.84 (m, 1H), 2.65-2.62 (m, 1H), 1.98-1.90 (m,1H), 1.85-1.77 (m, 1H), 1.05-0.70 (m, 6H), 0.35-0.33 (m, 2H), 0.02-0.00(m, 2H). MS (APCI+) [M+H] ⁺470.

Example 34

2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.40 (m, 1H), 7.47-7.43 (m, 1H), 7.16-7.14 (d,J=9.6 Hz, 1H), 7.06-7.04 (d, J=8.4 Hz, 1H), 5.30-5.25 (m, 1H), 4.38-4.35(m, 1H), 4.20-3.65 (m, 4H), 3.60-3.20 (m, 7H), 3.10-3.04 (m, 1H),2.22-2.18 (m, 1H), 2.10-1.98 (m, 1H), 1.20-1.10 (m, 6H), 1.08-0.96 (m,3H). MS (APCI+) [M+H] ⁺476.

Example 35

2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(pyrrolidin-1-yl)propan-1-one

Step 1:

Methyl 2-(4-chlorophenyl)acrylate (500 mg, 2.54 mmol) was diluted in THF(6.0 mL) and treated with pyrrolidine (233 uL, 2.80 mmol) at 0° C. After1 hour, the crude LCMS indicated that the reaction was complete (LCMS(APCI+) [M+H]⁺ 268.1; Rf: 2.13 min). The solution was treated with water(2.0 mL) and LiOH—H₂O (320 mg, 7.63 mmol), respectively, and thereaction was allowed to stir overnight to completion by LCMS analysis.The mixture was partitioned between water and ethyl acetate. The aqueouslayer was washed again with ethyl acetate, and the organics werediscarded. The aqueous layer was treated with excess 3N HCl solution(3.82 mL) and washed with ethyl acetate. The separated aqueous layer wasconcentrated in vacuo to afford the pure product (as a HCl-3LiCl salt)as a white solid (1.15 g). MS (APCI+) [M+H]⁺ 254.1; Rf: 1.30 min.

Step 2:

HBTU (37 mg, 0.098 mmol) was added to a solution of(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (30 mg, 0.098 mmol) and2-(4-chlorophenyl)-3-(pyrrolidin-1-yl)propanoic acid hydrochloride-3LiClcomplex (83 mg) in DCM (4 mL) and TEA (1 mL). The mixture was stirred atroom temperature for 2 hours. The solvent was removed, and the residuewas subject to column chromatography, eluted by EtOAc-DCM/MeOH (10:1).The product was treated with HCl to afford2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(pyrrolidin-1-yl)propan-1-oneas the HCl salt (12 mg, 26%).

¹H NMR (CDCl₃, 400 MHz) δ 8.46 (s, 1H), 7.83-7.81 (d, J=8.4 Hz, 1H),7.63-7.61 (d, J=8.0 Hz, 1H), 7.31-7.23 (m, 2H), 5.11-4.98 (m, 2H),3.95-3.90 (m, 1H), 3.80-3.00 (m, 10H), 2.20-1.90 (m, 7H), 1.32-1.20 (m,3H), 1.12-1.08 (m, 4H). MS (APCI+) [M+H] ⁺470.

Example 36

(R)-2-amino-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one

MS (APCI+) [M+H] ⁺416.

Example 37

2-(4-chlorophenyl)-1-((S)-4-((S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-3-(isopropylamino)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.10-8.00 (m, 1H), 7.10-6.85 (m, 2H), 6.80-6.70(m, 2H), 4.82-4.70 (m, 1H), 4.00-2.50 (m, 12H), 2.10-1.90 (m, 1H),1.50-1.40 (m, 1H), 0.90-0.70 (m, 9H). MS (APCI+) [M+H] ⁺458.

Example 38

(R)-2-amino-3-(4-chlorophenyl)-1-((S)-4-((R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.50-8.40 (m, 1H), 7.40-7.10 (m, 4H), 5.25-5.10(m, 1H), 4.00-2.90 (m, 14H), 2.52-2.40 (m, 1H), 1.95-1.80 (m, 1H),1.20-1.10 (m, 3H). MS (APCI+) [M+H] ⁺416.

Example 39

(R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.55-8.40 (m, 1H), 7.40-6.90 (m, 3H), 5.25-5.10(m, 1H), 4.00-2.90 (m, 14H), 2.52-2.40 (m, 1H), 1.95-1.80 (m, 1H),1.20-1.10 (m, 3H). MS (APCI+) [M+H] ⁺434.

Example 40

2-(4-chlorophenyl)-1-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one

Step 1:

A solution of (R)-tert-butyl4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(40 mg, 0.120 mmol) in THF (4 mL) was added to a 1.5M solution ofmethyllithium in diethyl ether (0.088 mL, 0.132 mmol) at −78° C. Theresulting mixture was stirred at −78° C. for 1 hour and quenched bysaturated aqueous NH₄Cl. The aqueous layer was extracted with EtOAc(2×). The organic layer was dried (MgSO₄) and concentrated. The residuewas purified by a silica cartridge (5.0 g) eluted by EtOAc to givetert-butyl4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylateas an off-white solid (29 mg, 69%). LCMS (APCI+) [M−Boc+H]+ 349.1; Rt:2.49 min.

Step 2:

A solution of tert-butyl4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate(28 mg, 0.080 mmol) in DCM (6 mL) was added to a 4.0M HCl solution indioxane (1.4 mL, 5.63 mmol). The mixture was stirred at room temperaturefor 4 hours. A 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol) from adifferent bottle was added. The resulting mixture was stirred for 18hours. The solvents were removed in vacuo to give(5R)-5,7-dimethyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride. DIPEA (41.5 mg, 0.321 mmol) was added to a suspensionof this(5R)-5,7-dimethyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (25.8 mg, 0.0803 mmol),3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid(32.9 mg, 0.0964 mmol), andO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (36.6 mg, 0.0964 mmol) in CH₂Cl₂ (6 mL) at roomtemperature. The resulting mixture was stirred for 1 hour. The solventwas removed in vacuo. The residue was purified by a silica cartridge(5.0 g) eluted by EtOAc to give tert-butyl2-(4-chlorophenyl)-3-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate(46 mg, 100%) as a gel. LCMS (APCI+) [M−Boc+H] ⁺472.2; Rt: 3.51 min.

Step 3:

A solution of tert-butyl2-(4-chlorophenyl)-3-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate(46 mg, 0.080 mmol) in DCM (6 mL) was added to a 4.0M HCl solution indioxane (1.4 mL, 5.63 mmol). The mixture was stirred at room temperaturefor 16 hours. The solvents were removed in vacuo to give2-(4-chlorophenyl)-1-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onedihydrochloride (49 mg, 100%) as a mixture of diastereomers. Rt: 2.05and 2.18 min.

LCMS (APCI+) [M+H] ⁺472.

Example 41

(R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one

¹H NMR (D₂O, 400 MHz) δ 8.39 (s, 1H), 7.38-7.36 (d, J=8.0 Hz, 2H),7.23-7.20 (d, J=8.4 Hz, 2H), 5.29-5.25 (m, 1H), 4.33-4.29 (m, 1H),4.09-3.90 (m, 2H), 3.82-3.10 (m, 10H), 2.23-2.17 (m, 1H), 2.07-1.98 (m,1H), 1.20-1.18 (m, 6H), 1.03-1.01 (d, J=6.8 Hz, 3H). MS (APCI+) [M+H]⁺458.

Example 42

(4-(3,4-dichlorophenyl)piperidin-4-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanonedihydrochloride

¹H NMR (D₂O, 400 MHz) δ 8.36 (m, 1H), 7.25-7.00 (m, 3H), 5.28-5.20 (m,1H), 4.00-3.00 (m, 14H), 2.50-2.38 (m, 2H), 2.26-2.00 (m, 2H), 1.04-1.00(m, 3H). MS (APCI+) [M+H] ⁺490.

Example 43

4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanonedihydrochloride

¹H NMR (D₂O, 400 MHz) δ 8.44-8.10 (m, 1H), 7.48-7.40 (m, 2H), 7.24-7.12(m, 1H), 5.33-5.28 (m, 1H), 4.00-3.85 (m, 1H), 3.80-3.00 (m, 11H),2.26-2.20 (m, 1H), 2.10-2.00 (m, 1H), 1.08-1.00 (m, 3H). MS (APCI+)[M+H] ⁺476.

Example 44

1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-one

¹H NMR (CDCl₃, 400 MHz) δ 8.46 (s, 1H), 7.83-7.81 (d, J=8.4 Hz, 1H),7.63-7.61 (d, J=8.0 Hz, 1H), 7.31-7.23 (m, 2H), 5.11-4.98 (m, 2H),3.95-3.90 (m, 1H), 3.80-3.00 (m, 10H), 2.20-1.90 (m, 7H), 1.32-1.20 (m,3H), 1.12-1.08 (m, 4H). MS (APCI+) [M+H] ⁺466.

Example 45

2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(2,2,2-trifluoroethylamino)propan-1-one

Step 1:

A solution of 2-(4-chlorophenyl)acetic acid (20.0 g, 117 mmol) in drymethanol (235 mL) was treated with 5 drops of concentrated H₂SO₄ (cat.)at room temperature. The mixture was stirred overnight to completion,and then concentrated in vacuo to about 40 milliliters. The concentratewas partitioned between ether and half saturated NaHCO₃ solution. Theaqueous portion was back-extracted once with ether, and the organicswere combined. The organic portion was washed with water, then brine,dried over MgSO₄, and concentrated in vacuo. The material was placedunder high vacuum for one hour to afford the pure methyl2-(4-chlorophenyl)acetate as a pale yellow oil (19.8 g, 92%). ¹H NMR(CDCl₃, 400 MHz) δ 7.30 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 3.70(s, 3H), 3.60 (2, 2H).

Step 2:

n-BuLi (1.60M in hexanes, 35.6 mL, 56.9 mmol) was added to a 0° C.solution of diisopropylamine (8.35 mL, 59.6 mmol) in THF (200 mL). Themixture was allowed to stir at 0° C. for 30 minutes, and was then cooledto −78° C. A solution of methyl 2-(4-chlorophenyl)acetate (10.0 g, 54.2mmol) in THF (10 mL) was added to the −78° C. LDA solution by syringe,which was then stirred for 45 minutes. Neat tert-butyl bromoacetate(9.60 mL, 65.0 mmol) was added by syringe, and the reaction was stirredfor 15 minutes at −78° C. The bath was removed, and the reaction wasallowed to warm to room temperature. After stirring an additional 5hours, the reaction mixture was quenched with saturated NH₄Cl solution,and the solvent(s) were removed in vacuo. The oily mixture was extractedwith ethyl acetate, and the organics were combined. The organic portionwas dried over MgSO₄, filtered, and concentrated in vacuo. The crude oilwas purified on silica gel (95:5 hexanes:EtOAc) to afford the4-tert-butyl 1-methyl 2-(4-chlorophenyl)succinate as a pale yellow oil(14.3 g, 88%). ¹H NMR (CDCl₃, 400 MHz) δ 7.29 (d, J=7.2 Hz, 2H), 7.22(d, J=7.2 Hz, 2H), 4.00 (dd, J=9.6, 5.6 Hz, 1H), 3.67 (s, 3H), 3.07 (dd,J=16.4, 9.6 Hz, 1H), 2.58 (dd, J=16.8, 6.0 Hz, 1H), 1.40 (m, 3H).

Step 3:

A solution of 4-tert-butyl 1-methyl 2-(4-chlorophenyl)succinate (14.3 g,47.7 mmol) in DCM (75 mL) was treated with neat TFA (75 mL) at roomtemperature. The mixture was stirred for five hours to completion, afterwhich the reaction mixture was concentrated and dried in vacuo overnightto afford a white solid. The solid was suspended in toluene (160 mL),cooled to 0° C., and treated successively with diphenylphosphoryl azide(11.2 mL, 52.1 mmol) and triethylamine (13.2 mL, 94.7 mmol). Thereaction mixture (homogeneous) was allowed to warm to room temperatureand stirred for four hours to completion. The solution was quenched with1% citric acid solution and extracted with EtOAc (3×). The combinedorganic portion was washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to give a light brown oil. The crude azide wasdissolved in tert-butanol (160 mL), treated with neat SnCl₄ (1.0Msolution, 2.37 mL, 2.37 mmol), and carefully heated to 90° C. withevolution of nitrogen. The mixture was stirred at 90° C. for 2.5 hoursand cooled to room temperature. The solution was quenched with saturatedNaHCO₃ solution and then concentrated. The oily mixture was extractedwith EtOAc (3×), and the combined organic portion was washed with brine,dried over MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by on silica gel (4:1 hexanes:EtOAc) to afford the methyl3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoate as a paleyellow oil (11.7 g, 79%). ¹H NMR (CDCl₃, 400 MHz) δ 7.31 (d, J=8.0 Hz,2H), 7.20 (d, J=8.0 Hz, 2H), 4.86 (br s, 1H), 3.88 (m, 1H), 3.69 (s,3H), 3.58 (m, 1H), 3.49 (m, 1H), 1.42 (s, 9H).

Step 4:

A solution of methyl3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoate (451 mg, 1.44mmol) in dioxane (6.0 mL) was treated with 4M HCl in dioxane (about 6.0mL, 23.0 mmol) at room temperature. The mixture was stirred for 18 hoursto completion, after which the reaction mixture was diluted with etherto afford a precipitate. The slurry was filtered under nitrogen toafford a white solid, which was washed with ether. The solid was driedunder vacuum to afford the methyl 3-amino-2-(4-chlorophenyl)propanoatehydrochloride as a white solid (321 mg, 89%). LCMS (APCI+) m/z 214.0[M+H]⁺.

Step 5:

A solution of methyl 3-amino-2-(4-chlorophenyl)propanoate hydrochloride(215 mg, 0.86 mmol) in 1:1 THF:DMF (3.0 mL) was treated with DIEA (389uL, 2.23 mmol) at room temperature. Trifluoroethyl triflate (299 mg,1.29 mmol) was added to the mixture, and the reaction was stirred for 20hours to completion. The mixture was partitioned between ethyl acetateand diluted NaHCO₃ solution. The aqueous portion was extracted twice,and the combined organic portions were washed with water (3×). Theorganic portion was washed with brine, separated, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography (silica gel eluted with 4:1 hexanes:ethyl acetate,Rf=0.18) to afford the pure methyl2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoate (235 mg, 93%)as a colorless oil. LCMS (APCI+) m/z 296.0 [M+H]⁺.

Step 6:

A solution of methyl2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoate (235 mg,0.795 mmol) in THF (3.0 mL) was treated with KOTMS (153 mg, 1.19 mmol)at room temperature. The reaction was allowed to stir 18 hours tocompletion, and the mixture was diluted with ether. The resultingprecipitate was isolated by filtration and placed under high vacuum fortwo hours to afford the potassium2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoate (299 mg,118%, excess salts) as a white solid. LCMS (APCI+) m/z 282.0 [M+H]⁺.

Step 7:

A solution of(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (30 mg, 98 umol) and potassium2-(4-chlorophenyl)-3-(2,2,2-trifluoroethylamino)propanoate (31.2 mg, 98umol) in DMF (1.0 mL) was treated with DIEA (36 uL, 205 umol) and HBTU(41 mg, 107 umol), respectively, at room temperature. The mixture wasallowed to stir for 18 hours to completion, and the solution waspartitioned between ethyl acetate and water. The aqueous portion wasextracted twice, and the organics were combined. The organic portion waswashed with water (3×), then brine, separated, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified bychromatography (silica gel eluted with 9:1 ethyl acetate:MeOH) to affordthe pure free-base as a colorless oil. This material was dissolved inether (1.0 mL), then treated with excess 2.0M HCl in ether. Thesuspension was concentrated in vacuo to afford the pure2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(2,2,2-trifluoroethylamino)propan-1-onedihydrochloride (31 mg, 99%) as a white solid. LCMS (APCI+) m/z 498.2[M+H]+.

Example 46

3-(tert-butylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one

Step 1:

A stirring solution of methyl 2-(4-chlorophenyl)acetate (36.7 g, 199mmol) (From Example 1, Step 1) and paraformaldehyde (6.27 g, 209 mmol)in DMSO (400 mL) was treated with sodium methoxide (537 mg, 9.94 mmol)at room temperature. The mixture was allowed to stir for two hours tocompletion and then poured into ice-cold water (700 mL) forming a whiteemulsion. The quench was neutralized with the addition of 1M HClsolution, and the aqueous was extracted with ethyl acetate (3×). Thecombined organic portions were washed with water (2×), then brine, driedover MgSO₄, and concentrated in vacuo. The residue was filtered througha plug of silica gel eluted stepwise with 9:1 to 1:1 hexanes:ethylacetate to afford the pure methyl 2-(4-chlorophenyl)-3-hydroxypropanoate(39.4 g, 92%) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.32 (d,J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 4.10 (m, 1H), 3.82 (m, 2H), 3.72(s, 3H), 2.25 (m, 1H).

Step 2:

A solution of methyl 2-(4-chlorophenyl)-3-hydroxypropanoate (39.4 g, 184mmol) in DCM (500 mL) was treated with triethylamine (64.0 mL, 459 mmol)and cooled to 0° C. The solution was treated with methanesulfonylchloride (15.6 mL, 202 mmol) slowly, then allowed to stir for 30 minutesto completion. The solution was partitioned with 1N HCl solution, andthe aqueous portion was back-extracted once with DCM. The combinedorganic portions were washed again with 1N HCl solution, separated, thenwashed with a half saturated NaHCO₃ solution. The organic portion wasdried over MgSO₄ and concentrated in vacuo to afford an orange oil. Theresidue was filtered through a plug of silica gel eluted with 9:1hexanes:ethyl acetate to afford the pure methyl2-(4-chlorophenyl)-3-hydroxypropanoate (30.8 g, 85%) as a colorless oil.¹H NMR (CDCl₃, 400 MHz) δ 7.36 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz,2H), 6.38 (s, 1H), 5.90 (s, 1H), 3.82 (s, 3H).

Step 3:

A solution of methyl 2-(4-chlorophenyl)acrylate (2.00 g, 10.2 mmol) in1:1 THF:ethanol (20 mL) was treated with tert-butyl amine (389 uL, 2.23mmol) at 60° C. The reaction stirred for 20 hours to completion, and thesolvent/excess amine were removed in vacuo. The residue was purified bychromatography on silica gel (eluted with 1:1 hexanes:ethyl acetate) toafford the pure methyl 3-(tert-butylamino)-2-(4-chlorophenyl)propanoate(2.54 g, 93%) as a colorless oil. LCMS (APCI+) m/z 270.0 [M+H]⁺.

Step 4:

A solution of methyl 3-(tert-butylamino)-2-(4-chlorophenyl)propanoate(1.00 g, 3.71 mmol) in THF (15 mL) was treated with KOTMS (555 mg, 3.89mmol) at room temperature. The reaction was allowed to stir 18 hours tocompletion, and the mixture was concentrated in vacuo. The residue wasplaced under high vacuum for three hours to afford the near-purepotassium 3-(tert-butylamino)-2-(4-chlorophenyl)propanoate (1.06 g, 97%)as a white solid. This material was used without purification. LCMS(APCI+) m/z 256.0 [M+H]⁺.

Step 5:

A solution of(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (31.7 mg, 0.103 mmol) and potassium3-(tert-butylamino)-2-(4-chlorophenyl)propanoate (30.3 mg, 0.103 mmol)in DMF (1.0 mL) was treated with DIEA (38 uL, 0.217 mmol) and HBTU (43mg, 114 mmol), respectively, at room temperature. The mixture wasallowed to stir for 18 hours to completion, and the solution waspartitioned between ethyl acetate and water. The aqueous was extractedtwice, and the organics were combined. The organic portion was washedwith water (3×), then brine, separated, dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by reverse phasechromatography (eluted with water:acetonitrile gradients modified with1% ammonium acetate) to afford the pure3-(tert-butylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one(20 mg, 41%) as a white solid. LCMS (APCI+) m/z 472.2 [M+H]⁺.

Example 47

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)propan-1-one

37% w/w formaldehyde/H₂O (0.1489 ml, 2.000 mmol) was added to a solutionof(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-onedihydrochloride (0.115 g, 0.2000 mmol) and DIEA (0.105 mL, 0.600 mmol)in DCE (1.5 mL) and THF (0.5 mL), followed by addition of Na(OAc)₃BH(0.08477 g, 0.4000 mmol). The reaction mixture was stirred for 2 hours,and 1 equivalent of Na(OAc)₃BH was added. The reaction mixture wasstirred for 14 hours. Another 5 equivalents of formaldehyde solution and1.5 equivalents of Na(OAc)₃BH were added, and the reaction mixture wasstirred another 3 hours. Saturated NaHCO₃ was added, the mixture wasextracted with DCM, and the combined extracts were dried (Na₂SO₄),filtered, and concentrated. The crude was purified on silica usingBiotage 12M (1:1 DCM:EtOAc loaded and 125 mL flushed, then 25:1 to 10:1DCM:MeOH gradient), and fractions with product were concentrated. Theresulting residue was dissolved in minimal DCM/ether, and excess 2MHCl/ether was added, causing precipitation. The mixture was stirred for5 minutes, then concentrated to dryness and dried in vacuo. The solidswere suspended in ether and isolated by filtration through 20 μm nylonfilter paper with nitrogen pressure, rinsed with ether, and dried invacuo to give(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)propan-1-onedihydrochloride (0.080 g, 68.15% yield) as a white powder. LCMS (APCI⁺)m/z 514 [M+H]⁺.

Example 48

(S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one

Step 1:

Tert-butyl cyclopropylmethylcarbamate (11.2 g, 65.4 mmol) was dissolvedinto THF (60 mL) and set to stir at −78° C. BuLi (2.5M, 28.8 mL) wasthen added portionwise over 10 minutes. The reaction was allowed to stirwhile warming to −20° C. for 10 minutes, and continued stirring at thattemperature for another 10 minutes. The reaction was then recooled to−78° C. at which point chloro(methoxy)methane (5.79 g, 72.0 mmol) wasadded via syringe. The reaction was then allowed to stir overnight withwarming. The reaction was then quenched with 1 N HCl and the organiclayer separated. The aqueous layer was then extracted with DCM (2×), andthe combined organic portions were dried with MgSO₄, filtered andconcentrated. The crude material was purified by passing through asilica plug eluting 10:1 Hex/EtOAc to give tert-butylcyclopropylmethyl(methoxymethyl)carbamate (12.8 g, 91%) as a clearliquid.

Step 2:

(R)-4-Benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (2.0 g, 6.06mmol) was added to a flask in DCM (75 ml) followed by TiCl₄ (1.38 g,7.28 mmol) and DIEA (0.823 g, 6.37 mmol). The reaction was allowed tostir for about 15 to about 20 minutes at −78° C. at which pointtert-butyl cyclopropylmethyl(methoxymethyl)carbamate (1.57 g, 7.28 mmol)was added. The reaction allowed to stir for 5 minutes, and the −78° C.bath was replaced with a 0° C. bath. The reaction was then allowed tostir for 3 hours at room temperature. After the reaction was determinedto be complete by HPLC, the reaction was cooled to 0° C. and quenched bythe slow addition of aqueous NaHCO₃ while stirring for 10 minutes. Theorganic layer was separated, and the aqueous layer was re-extracted(3×EtOAc). The combined organics were dried with MgSO₄, filtered andconcentrated. The crude residue was purified by column chromatography,eluting 6:1 to 2:1 hexane/EtOAc to give tert-butyl(S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(cyclopropylmethyl)carbamate(2.70 g, 87%) as light brown oil. (LCMS (APCI+) [M−Boc+H]⁺ 412.9; Rt:4.42 min)

Step 3:

LiOH (1.41 g, 33.5 mmol) was added to a flask containing THF (360 mL)and H₂O (120 mL), which was stirred until dissolved. At this point, thereaction was cooled to 0° C. with ice, and hydrogen peroxide (35 wt. %,6.52 g) was added. This solution was stirred for 10 minutes, at whichpoint tert-butyl(S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(cyclopropylmethyl)carbamate(8.6 g, 16.8 mmol) was added as a solution in THF (20 mL). The reactionwas stirred overnight with warming. The reaction was quenched by theaddition of 10% aqueous Na₂SO₃ (1 mL) and saturated aqueous NaHCO₃ (1mL) and stirred for 10 minutes. The reaction was concentrated to removeTHF and the aqueous layer extracted with ether (3×). The aqueous layerwas diluted with EtOAc and acidified with 1N HCl. The organic layer wasremoved, and the aqueous layer was extracted with EtOAc (2×). Thecombined organics were dried with MgSO₄ and concentrated to give thecrude product,(S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoicacid as a clear oil (LCMS (APCI+) [M−Boc+H]⁺ 254.1; Rt: 3.03 min).

Step 4:

Crude(S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoicacid (4.6 g, 13 mmol) was dissolved into DCM (130 mL) and excess 4N HClwas added. The reaction was allowed to stir overnight, after which itwas concentrated. The resulting white solid was taken up into EtOAC andfiltered. The resulting solid was washed with EtOAc (4×) to give pure(S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)propanoic acidhydrochloride (3.60 g, 95%). This(S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)propanoic acid (0.57 g,2.24 mmol) was dissolved into 10:1 CH₃CN:H₂O (50 mL) andtetramethylammonium hydroxide pentahydrate (1.00 g) was added followedby Boc2O (0.73 g, 3.36 mmol). The reaction mixture was allowed to stirat room temperature overnight, and the reaction was quenched by theaddition of 1N HCl. The reaction was concentrated, and the residue wasdiluted with EtOAc. The organics were separated, and the aqueous portionwas extracted with EtOAc. The combined organics were dried with MgSO₄,filtered and concentrated. The crude residue was purified by silica plugeluting Hex to 1:1 Hex/EtOAc to give(S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoicacid (0.58 g, 73%) as a clear oil. (LCMS (APCI+) [M−Boc+H]⁺ 254.0)

Step 5:

(5R,7S)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-oldihydrochloride (0.0444 g, 0.1445 mmol) and(S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoicacid (0.05114 g, 0.1445 mmol) were combined in methylene chloride (1.25mL). They were then treated with diisopropylethylamine (0.07552 ml,0.4336 mmol), followed by HBTU (0.05495 g, 0.1445 mmol). The reactionwas stirred at ambient temperature for 16 hours. The reaction wasquenched with 10% Na₂CO₃, diluted with methylene chloride and separated.The aqueous portion was washed with methylene chloride (2×), and thecombined organic layers were dried over Na₂SO₄ and concentrated invacuo. The material was chromatographed on SiO₂ (Biotage 12M) and elutedwith 4% MeOH/MC. The material was concentrated in vacuo to givetert-butyl(S)-2-(4-chlorophenyl)-3-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(cyclopropylmethyl)carbamateas a white solid (67.4 mg, 82%). LCMS (APCI+) [M+H]⁺ 570.0.

Step 6:

Tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(cyclopropylmethyl)carbamate(0.0674 g, 0.1182 mmol) was dissolved in dioxane (0.5 mL) and treatedwith HCl in dioxane (0.7389 ml, 2.956 mmol) (4M). The reaction wasstirred at ambient temperature for 48 hours. The reaction mixture wasconcentrated in vacuo. The residue was redissolved in MeOH andre-concentrated three times. This residue was resuspended in MeOH(0.2+0.1 mL) and added dropwise to a stirred flask of Et₂O (10 mL).After stirring for 30 minutes, the solids were filtered, washed withEt₂O, and dried under a blanket of nitrogen to give(S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-oneas a white solid (60.2 mg, 94%.) LCMS (APCI+) [M+H]⁺ 470.2.

Example 49

(S)-2-(5-chlorothiophen-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one

Step 1:

Triethylamine (7.32 mL, 52.5 mmol) was added to a solution of5-chlorothiophene-2-acetic acid (8.83 g, 50.0 mmol) in ether (200 mL) at−78° C., followed by 2,2-dimethylpropanoyl chloride (6.46 mL, 52.5mmol). The resulting mixture was stirred at 0° C. for 2 hours, and thenre-cooled to −78° C. Meanwhile, a solution of(R)-4-benzyl-2-oxazolidinone (9.30 g, 52.5 mmol) in THF (100 mL) in aseparated flask was cooled to −78° C. 2.5M of n-butyllithium in hexane(22.0 mL) was added dropwise. The resulting solution was stirred at −78°C. for 1 hour, and then added via cannula into the solution of the mixedanhydride. The reaction mixture was stirred at −78° C. for 15 minutes,at 0° C. for 30 minutes, then at room temperature overnight. SaturatedNHCl (300 mL) was added to quench the reaction. The mixture wasextracted with EtOAc (3×200 mL). The combined organics were dried(Na₂SO₄), filtered and concentrated. The crude product was purified bysilica gel chromatography, eluting with EtOAc/hexane (0-25%) to give(R)-4-benzyl-3-(2-(5-chlorothiophen-2-yl)acetyl)oxazolidin-2-one (9.43g, 56%). ¹H NMR (CDCl₃, 400 MHz) δ 7.33-7.25 (m, 3H), 7.16-7.13 (m, 2H),6.79-6.76 (m, 2H), 4.70-4.65 (m, 1H), 4.38 (q, J=17.2 Hz, 2H), 4.25-4.18(m, 2H), 3.27 (dd, J=13.6 Hz, J=3.6 Hz, 1H), 2.77 (dd, J=13.6 Hz, J=3.6Hz, 1H).

Step 2:

1.0M of titanium tetrachloride in DCM (30.9 mL, 30.9 mmol) was addeddropwise to a solution of(R)-4-benzyl-3-(2-(5-chlorothiophen-2-yl)acetyl)oxazolidin-2-one (9.43g, 28.1 mmol) in DCM (170 mL) at −78° C., followed byN,N-diisopropylethylamine (9.78 mL, 56.2 mmol). The resulting dark bluemixture was stirred at −78° C. for 1 hour. tert-Butylisopropyl(methoxymethyl)carbamate (11.4 g, 56.2 mmol) was then added.The mixture was stirred at −78° C. for 1 hour, and then allowed to warmup to room temperature. The mixture was stirred at room temperature for2 hours, quenched with saturated NH₄Cl (300 mL), and extracted with DCM(3×200 mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by silica gelchromatography eluting with EtOAc/hexane (0-20%) to give tert-butyl(S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(5-chlorothiophen-2-yl)-3-oxopropyl(isopropyl)carbamate(10.2 g, 72%). MS (APCI+) [M+H]⁺ 507.2. ¹H NMR (CDCl₃, 400 MHz) δ7.36-7.22 (m, 5H), 6.79 (d, J=4.0 Hz, 1H), 6.75 (d, J=4.0 Hz, 1H).4.67-4.62 (m, 1H), 4.15-4.09 (m, 4H), 3.45-3.38 (m, 2H), 2.80-2.72 (m,1H), 1.49 (s, 9H), 1.12 (d, J=6.0 Hz, 3H), 1.05 (d, J=6.0 Hz, 3H).

Step 3:

A mixture solution of lithium hydroxide (374 mg, 15.6 mmol) in H₂O (60mL) and 30% hydrogen peroxide (1.60 mL, 15.6 mmol) was added dropwise toa solution of tert-butyl(S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(5-chlorothiophen-2-yl)-3-oxopropyl(isopropyl)carbamate(7.54 g, 14.9 mmol) in THF (150 mL) at −5° C. The mixture was stirred at−5° C. After 10 minutes, the reaction was quenched with 10% Na₂SO₃ (16mL) at −5° C. and stirred at room temperature for 30 minutes. The THFwas removed in vacuo. The aqueous layer was acidified with 1M NaH₂PO₄and extracted with DCM (3×100 mL). The combined organics were dried(Na₂SO₄), filtered and concentrated to give(S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(5-chlorothiophen-2-yl)propanoicacid which was used in the next step without purification. MS (APCI+)[M+H]+ 348.2.

Step 4:

A solution of(5R,7R)-5-methyl-4-((S)-piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-olditrifluoroacetic acid (351 mg, 1.50 mmol) and N,N-diisopropylethylamine(2.61 mL, 15.0 mmol) in DCM (5 mL) was added to a solution of(S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(5-chlorothiophen-2-yl)propanoicacid (0.522 g, 1.50 mmol) in DCM (5 mL) and DMF (1 mL), followed byO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(0.597 g, 1.57 mmol). The mixture was stirred at room temperature for 1hour. The reaction was quenched with saturated NH₄Cl (20 mL) andextracted with DCM (2×20 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude product was purified by silica gelchromatography eluting first with EtOAc/hexane (0-100%), then withMeOH/DCM (0-6%) to give tert-butyl(S)-2-(5-chlorothiophen-2-yl)-3-(4-((5R,7R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylisopropylcarbamate(535 mg, 63%). MS (APCI+) [M+H]+ 564.0. ¹H NMR (CDCl₃, 400 MHz) δ8.53(s, 1H), 6.75 (d, J=4.0 Hz, 1H), 6.68 (d, J=4.0 Hz, 1H), 5.11 (t, J=6.8Hz, 1H), 4.94 (brs, 1H), 3.83-3.35 (m, 13H), 2.24-2.12 (m, 2H), 1.49 (s,9H), 1.18 (d, J=7.2 Hz, 3H), 1.01 (d, J=6.0 Hz, 3H), 0.82 (d, J=6.0 Hz,3H).

Step 5:

4.0M hydrogen chloride in 1,4-dioxane (2.508 mL) was added to a solutionof tert-butyl(S)-2-(5-chlorothiophen-2-yl)-3-(4-((5R,7R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylisopropylcarbamate(283 mg, 0.502 mmol) in 1,4-dioxane (2.5 mL) and methylene chloride (2.5mL) at 0° C. The mixture was allowed to warm up to room temperature andstirred for 1 hour. The mixture was concentrated in vacuo. The residuewas then dissolved in a minimum volume of DCM (1 mL) and added dropwiseto ether (10 mL) at 0° C. with stirring. A white solid precipitated. Thesolvents were evaporated with a rotovap in a 25° C. bath. The off-whitesolid was dried under high vacuum overnight to give(S)-2-(5-chlorothiophen-2-yl)-1-(4-((5R,7R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-onedihydrochloride (537 mg, 99.9%). MS (APCI+) [M+H]+ 464.1. ¹H NMR (D20,400 MHz) δ 8.53 (s, 1H), 6.97 (d, J=4.0 Hz, 1H), 6.96 (d, J=4.0 Hz, 1H),5.40 (t, J=8.0 Hz, 1H), 4.78-4.71 (m, 1H), 4.31-4.27 (m, 1H), 4.09-3.97(m, 2H), 3.84-3.42 (m, 10H), 2.36-2.30 (m, 1H), 2.21-2.13 (M, 1H), 1.33(d, J=6.4 Hz, 3H), 1.32 (d, J=6.4 Hz, 3H), 1.14 (d, J=6.4 Hz, 3H).

Examples 50-324 shown in Table 1 can also be made according to theabove-described methods.

TABLE 1 Example Structure Name LCMS or ¹H NMR 50

(R)-2-amino-3-(4-chlorophenyl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)propan-1-one416.2 51

1-(4-((5R,7R)-7-hydroxy-5-methyl- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- (isopropylamino)-2-(4-(trifluoromethyl)phenyl)propan-1-one 492.2 52

4-(1-(4-((5R,7R)-7-hydroxy-5-methyl- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(isopropylamino)-1-oxopropan-2- yl)benzonitrile 449.2 53

(S)-2-(4-chlorophenyl)-1-(4-((5R,7S)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 458.3 54

3-(azetidin-1-yl)-2-(4-chlorophenyl)- 1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)propan-1-one456.2 55

2-(4-chlorophenyl)-1-(4-((5R,7R)-7- hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(3-hydroxyazetidin-1-yl)propan-1-one 472.2 56

2-(4-chlorophenyl)-1-(4-((5R,7R)-7- hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(neopentylamino)propan-1-one 486.3 57

2-(4-bromophenyl)-1-(4-((5R,7R)-7- hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 504.2 58

2-(4-chlorophenyl)-3-(4- fluoropiperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 502.2 59

2-(4-chlorophenyl)-3-((S)-3- fluoropyrrolidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 488.2 60

2-(4-chlorophenyl)-3-(ethylamino)-1- (4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)propan-1-one444.3 61

2-(4-chlorophenyl)-1-(4-((5R,7R)-7- hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1- one 472.2 62

2-(4-chlorophenyl)-3-(4,4- difluoropiperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 520.2 63

2-(4-chlorophenyl)-3-(3,3- difluoropyrrolidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 506.2 64

2-(4-bromo-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 520.2 65

(R)-2-amino-3-(4-fluorophenyl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)propan-1-one400.2 66

(R)-2-amino-3-(3,4-dichlorophenyl)- 1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)propan-1-one450.2 67

(R)-2-amino-3-(3,4-difluorophenyl)- 1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)propan-1-one418.2 68

(R)-2-(4-chlorophenyl)-3- (cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one m/z 470 [M + H]+ 69

(S)-2-(4-chlorophenyl)-3- (cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one m/z 470 [M + H]+ 70

2-(4-chlorophenyl)-3-((R)-3- fluoropyrrolidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 488.2 71

(S)-1-(4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- (isopropylamino)-2-(4-(trifluoromethoxy)phenyl)propan-1- one 508.3 72

(S)-2-(4-chlorophenyl)-3- (cyclopropylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 456.2 73

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(3-hydroxyazetidin-1-yl)propan-1-one 472.1 74

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(3-hydroxyazetidin-1-yl)propan-1-one 472.1 75

(R)-4-amino-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-methylpentan-1-one ¹H NMR(CD₃OD), 400 MHz, 8.51 (s, 1H), 7.40-7.33 (m, 4H), 5.17 (dd,J = 14.9, 7.04 Hz, 1H), 4.26 (dd, J = 9.4, 3.1 Hz, 1H), 4.06 (m, 1H),3.85-3.60 (bm, 7H), 3.42 (m, 1H), 2.76 (dd, J = 14.9, 10.1 Hz, 1H), 2.2(m, 2H), 1.81 (dd, J = 14.1, 3.1 Hz, 1H), 1.35 (s, 3H), 1.32 (s, 3H),1.15 (d, J = 7.04 Hz, 3H). 76

(S)-4-amino-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-methylpentan-1-one ¹H NMR(CD₃OD), 400 MHz, 8.51 (s, 1H), 7.40-7.32 (m, 4H), 5.17 (dd,J = 14.9, 7.04 Hz, 1H), 4.25 (dd, J = 9.4, 3.1 Hz, 1H), 4.03-3.52 (bm,8H), 3.30 (m, 1H), 2.75 (dd, J = 14.9, 9.4 Hz, 1H), 2.18 (m, 2H), 1.82(dd, J = 14.1, 3.1 Hz, 1H), 1.35 (s, 3H), 1.32 (s, 3H), 1.18 (d, J = 6.3Hz, 3H) 77

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-((R)-pyrrolidin-3-ylamino)propan-1-one 485.2 78

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-((S)-pyrrolidin-3-ylamino)propan-1-one 485.2 79

(S)-3-((R)-1-acetylpyrrolidin-3- ylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 527.2 80

(S)-3-((S)-1-acetylpyrrolidin-3- ylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 527.2 81

(S)-2-(4-bromophenyl)-3- (cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 514.0 82

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(piperidin-4-ylamino)propan-1-one m/z 499 [M + H]+ 83

(S)-3-(1-acetylpiperidin-4-ylamino)-2- (4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one m/z 541 [M + H]+ 84

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(2-methoxyethylamino)propan-1-one m/z 474 [M + H]+ 85

(R)-2-(4-chlorophenyl)-4- (dimethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one 458.1 86

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one m/z 500 [M + H]+ 87

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-((1r,4S)-4-hydroxycyclohexylamino)propan-1- one 514.3 88

(S)-3-(azetidin-1-yl)-2-(4- chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 456.3 89

(R)-3-(azetidin-1-yl)-2-(4- chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 456.3 90

2-((S)-2-(4-chlorophenyl)-3-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-oxopropylamino)acetamide 473.2 91

2-((S)-2-(4-chlorophenyl)-3-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-oxopropylamino)-N,N- dimethylacetamide 501.3 92

2-((S)-2-(4-chlorophenyl)-3-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-oxopropylamino)-N-methylacetamide 487.2 93

(R)-2-(4-bromophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-(isopropylamino)butan-1-one 516.2/518.1 94

(R)-2-(4-bromophenyl)-4- (dimethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one 502.1/504.1 95

(R)-2-(4-bromophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-(isobutylamino)butan-1-one 530.2 96

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-((2-methoxyethyl)(methyl)amino)butan-1- one 502.1 97

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-(isopropylamino)butan-1-one 472.2 98

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-(3-hydroxyazetidin-1-yl)butan-1-one 486.2 99

2-((R)-3-(4-bromophenyl)-4-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-oxobutylamino)-N,N- dimethylacetamide 559.1 100

(R)-2-(4-bromophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-(2-hydroxyethylamino)butan-1-one 518.2/520.1 101

(2R)-2-(4-bromophenyl)-4-(2- hydroxy-1-(tetrahydro-2H-pyran-4-yl)ethylamino)-1-(4-((5R,7R)-7- hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)butan-1-one 604.2 102

(R)-2-amino-1-(4-((5R,7R)-7- hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(4-iodophenyl)propan-1-one 508.1 103

4-((R)-2-amino-3-(4-((5R,7R)-7- hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- oxopropyl)benzonitrile407.2 104

(R)-2-amino-1-(4-((5R,7R)-7- hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)propan-1-one 450.2 105

(S)-3-(4-acetylpiperazin-1-yl)-2-(4- chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 527.2 106

(R)-3-(4-acetylpiperazin-1-yl)-2-(4- chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 527.2 107

(R)-3-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-2-(methylamino)propan-1-one 430.2 108

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(4-(2-hydroxyethyl)piperazin-1-yl)propan- 1-one 529.4 109

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-(2-hydroxyethyl)piperazin-1-yl)propan- 1-one 529.4 110

2-(4-chlorophenyl)-1-(4-((5R,7R)-7- hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(3-methoxyazetidin-1-yl)propan-1-one 486.2 111

(R)-2-(4-chlorophenyl)-4- (cyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one 512.3 112

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(tetrahydro-2H- pyran-4-ylamino)butan-1-one 514.2113

(2R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-(2-hydroxypropylamino)butan-1-one 488.2 114

(2R)-2-(4-chlorophenyl)-4-(2- hydroxy-1-(tetrahydro-2H-pyran-4-yl)ethylamino)-1-(4-((5R,7R)-7- hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)butan-1-one 558.2 115

(2R)-2-(4-chlorophenyl)-4-(2- hydroxy-1-phenylethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one 550.2 116

(S)-2-(4-chlorophenyl)-3- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-1-(4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)propan-1-one m/z 528 [M +H]+ 117

(R)-2-(4-bromophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-(2-methoxyethylamino)butan-1-one 534.1 118

(2R)-2-(4-bromophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(3,3,3-trifluoro-2-hydroxypropylamino)butan-1-one 586.2 119

(R)-2-(4-bromophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-((1-hydroxycyclopropyl)methylamino) butan-1-one 544.2/546.2 120

2-((R)-3-(4-bromophenyl)-4-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-4-oxobutylamino)acetamide 531.1/533.1 121

(R)-2-(4-bromophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(tetrahydro-2H- pyran-4-ylamino)butan-1-one 558.2122

(R)-4-(3-(1H-imidazol-1- yl)propylamino)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)butan-1-one 584.2 123

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- morpholinopropan-1-one486.3 124

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-morpholinopropan-1-one 486.3 125

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one 499.4 126

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one 499.4 127

(S)-3-(3-aminoazetidin-1-yl)-2-(4- chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 471.2 128

(R)-3-(3-aminoazetidin-1-yl)-2-(4- chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 471.2 129

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-thiomorpholinopropan-1-one 502.2 130

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(piperazin-1-yl)propan-1-one 485.3 131

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(piperazin-1-yl)propan-1-one 485.3 132

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-thiomorpholinopropan-1-one 502.2 133

(R)-2-(4-chlorophenyl)-3-(4- fluoropiperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 502.2 134

(S)-2-(4-chlorophenyl)-3-(4- fluoropiperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 502.2 135

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(3-methoxyazetidin-1-yl)propan-1-one 486.2 136

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(3-methoxyazetidin-1-yl)propan-1-one 486.2 137

(S)-2-(3,4-dichlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 492.2 138

(S)-2-(4-chlorophenyl)-3- (dimethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 444.1 139

(S)-2-(4-fluoro-3- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one 510.2 140

(S)-2-(3-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one 510.4 141

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(methoxyamino)propan-1-one 446.2 142

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(4-methoxypiperidin-1-yl)propan-1-one 514.3 143

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-methoxypiperidin-1-yl)propan-1-one 514.3 144

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one 500.3 145

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one 500.3 146

(S)-3-(4-aminopiperidin)-1-yl)-2-(4- chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-propan-1-one 499.3 147

(R)-3-(4-aminopiperidin)-1-yl)-2-(4- chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-propan-1-one 499.3 148

(S)-2-(4-chlorophenyl)-1-(4-((5R,7S)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one 500.2 149

(S)-2-(4-chlorophenyl)-1-(4-((5R,7S)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(methyl(tetrahydro-2H-pyran-4- yl)amino)propan-1-one m/z 514 [M + H]+150

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1- one 472.3 151

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-(methylsulfonyl)piperazin-1- yl)propan-1-one 563.2 152

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(4-(methylamino)piperidin-1-yl)propan- 1-one 513.3 153

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-(methylamino)piperidin-1-yl)propan- 1-one 513.3 154

(S)-2-(4-chloro-3- (trifluoromethoxy)phenyl)-1-(4-(5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one 542.2 155

(S)-2-(3-fluoro-4- (trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one 526.3 156

(S)-2-(4-chloro-3- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one 526.2 157

(R)-2-(4-chlorophenyl)-3-(4- ethylpiperazin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 513.3 158

(S)-2-(4-chlorophenyl)-3-(4- ethylpiperazin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 513.3 159

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one 527.6 160

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one 527.6 161

(R)-2-(4-chlorophenyl)-3-((S)-3- (dimethylamino)pyrrolidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 513.6 162

(S)-2-(4-chlorophenyl)-3-((S)-3- dimethylamino)pyrrolidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 513.6 163

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-((R)-tetrahydrofuran-3-ylamino)propan-1- one 486.2 164

(S)-2-(4-chlorophenyl)-1-(4-((5R,7S)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-((R)-tetrahydrofuran-3-ylamino)propan-1- one 486.2 165

(S)-2-(4-chlorophenyl)-3-(2- fluoroethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 462.2 166

(S)-2-(4-fluoro-3- (trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one 526.4 167

(S)-2-(3,5- bis(trifluoromethyl)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one 560.3 168

(S)-2-(3-fluoro-4-methoxyphenyl)-1- (4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 472.5 169

4-((R)-2-(4-chlorophenyl)-3-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-oxopropyl)piperazin-2-one 499.3 170

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-((R)-3-hydroxypyrrolidin-1-yl)propan-1-one 486.3 171

(S)-2-(4-chlorophenyl)-3-(4- (dimethylamino)piperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 527.3 172

(R)-2-(4-chlorophenyl)-3-(4- (dimethylamino)piperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 527.3 173

(S)-2-(3-chloro-5-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 476.2 174

(S)-2-(3-bromo-4-methoxyphenyl)-1- (4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 532.2 175

(R)-3-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-2-(piperidin-4-ylamino)propan-1-one 499.3 176

(R)-2-(1-acetylpiperidin-4-ylamino)- 3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 541.3 177

2-((R)-3-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-1-oxopropan-2-ylamino)-N-isopropylacetamide 515.3 178

(R)-3-(4-chlorophenyl)-2- (dimethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 444.2 179

(R)-3-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-2-(2-morpholinoethylamino)propan-1-one 529.3 180

(R)-3-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-2-(isopropylamino)propan-1-one 458.2 181

(R)-3-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(tetrahydro-2H- pyran-4-ylamino)propan-1-one500.3 182

(R)-3-(4-chlorophenyl)-1-((S)-4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)-3-methylpiperazin-1-yl)-2-(isopropylamino)propan-1-one 472.3 183

2-((R)-3-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-1-oxopropan-2-ylamino)-N,N-dimethylacetamide 501.2 184

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(1,4-oxazepan-4-yl)propan-1-one 500.3 185

(R)-2-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(1,4-oxazepan-4-yl)propan-1-one 500.3 186

(R)-2-(4-chloro-2-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 476.2 187

(S)-2-(4-chloro-2-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 476.2 188

(S)-2-(2-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one 510.2 189

(S)-2-(4-chlorophenyl)-3- (cyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 498.3 190

(S)-2-(4-chlorophenyl)-3- (cyclohexylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 498.3 191

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(4-methoxycyclohexylamino)propan-1- one 528.4 192

(S)-2-(3-fluoro-4- (trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one568.3 193

(S)-2-(3-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one552.2 194

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-((S)-tetrahydrofuran-3-ylamino)propan-1- one 486.3 195

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(4-methyltetrahydro-2H-pyran-4- ylamino)propan-1-one 513.2 196

(R)-3-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)propan-1- one 528.3 197

(R)-3-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-2-(3,3,3-trifluoropropylamino)propan-1-one 512.2 198

(R)-3-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)methylamino)propan- 1-one 514.2 199

(R)-3-(4-chlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-2-(isopropyl(methyl)amino)propan-1- one 472.3 200

(S)-3-(tert-butylamino)-2-(4- chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 472.1 201

(R)-3-(tert-butylamino)-2-(4- chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 472.1 202

(S)-2-(4-chloro-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one 517.2 203

(R)-2-(4-chloro-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one 517.2 204

(S)-2-(4-chloro-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one 518.2 205

(R)-2-(4-chloro-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-morpholinopropan-1-one 504.2 206

(R)-2-(4-chloro-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one 518.2 207

(S)-2-(3-fluoro-4- (trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4- methylpiperazin-1-yl)propan-1-one 567.2 208

(R)-2-(3-fluoro-4- (trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4- methylpiperazin-1-yl)propan-1-one 567.2 209

(S)-3-(cyclopropylmethylamino)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1- (4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)propan-1-one522.2 210

(S)-3-(cyclopropylmethylamino)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 538.2 211

(S)-1-(4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3- (isopropylamino)-2-(4-(trifluoromethyl)phenyl)propan-1-one 492.3 212

(S)-3-amino-2-(4-bromophenyl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)propan-1-one m/z460/462 (Br isotope) [M + H]+ 213

(S)-3-amino-2-(4-chloro-3- fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one m/z 434 [M + H]+ 214

(S)-2-(4-bromophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one 546.2 215

3-((S)-2-(4-chlorophenyl)-3-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-oxopropylamino)propanamide 487.2 216

3-((S)-2-(4-chlorophenyl)-3-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-oxopropylamino)propanamide 487.2 217

(4-(4-chlorophenyl)piperidin-4-yl)(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)methanone 456.2218

(S)-2-(4-bromophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 504.2 219

(S)-3-amino-2-(4-chloro-3- fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 434.3 220

(S)-3-amino-2-(4-bromophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)propan-1-one462.2 221

(S)-2-(4-bromophenyl)-1-(4-((5R,7S)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one m/z 544/546 (Br isotope) [M + H]+ 222

(S)-2-(4-chloro-3-fluorophenyl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one m/z518 [M + H]+ 223

(S)-2-(3,4-dichlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one534.2 224

(S)-3-amino-2-(3,4-dichlorophenyl)- 1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)propan-1-one450.3 225

(R)-2-(3,4-dichlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one 534.2 226

(S)-2-(3,4-dichlorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one 561.3 227

(S)-2-(3-fluoro-4- (trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4- hydroxypiperidin-1-yl)propan-1-one 568.2 228

(R)-2-(3-fluoro-4- (trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4- hydroxypiperidin-1-yl)propan-1-one 568.2 229

(S)-2-(3-fluoro-4- (trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4- isopropylpiperazin-1-yl)propan-1-one 595.3230

(S)-2-(3,5-difluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 460.3 231

(S)-3-((R)-3-aminopyrrolidin-1-yl)-2- (4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 485.3 232

(R)-3-((R)-3-aminopyrrolidin-1-yl)-2- (4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 485.3 233

(S)-2-(4-chloro-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one 545.3 234

(S)-2-(3-fluoro-4- (trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- morpholinopropan-1-one 554.3 235

(R)-2-(3-fluoro-4- (trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- morpholinopropan-1-one 554.3 236

(S)-3-(4-ethylpiperazin-1-yl)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 581.3 237

(R)-3-(4-ethylpiperazin-1-yl)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 581.3 238

(S)-3-(4-acetylpiperazin-1-yl)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 595.3 239

(R)-3-(4-acetylpiperazin-1-yl)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 595.3 240

(S)-2-(3,4-dichlorophenyl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one534.2 241

(S)-2-(4-bromophenyl)-1-(4-((5R,7S)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one m/z 502/504 (Br isotope) [M + H]+ 242

(S)-2-(4-chloro-3-fluorophenyl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one m/z 476 [M + H]+ 243

(S)-2-(4-chloro-3-fluorophenyl)-3- (cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one m/z 488 [M + H]+ 244

(S)-3-(bis(cyclopropylmethyl)amino)- 2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one m/z 542 [M + H]+ 245

(S)-2-(4-bromophenyl)-3- (cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one m/z 514/516 (Br isotope) [M + H]+ 246

(S)-2-(4-chloro-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one LCMS(APCI+) m/z 518, 520 [M + H]+ 247

(S)-2-(4-chloro-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one LCMS (APCI+) m/z 476, 478 [M + H]+ 248

(S)-2-(4-bromophenyl)-3- ((cyclopropylmethyl)(methyl)amino)-1-(4-((5R,7S)-7-hydroxy-5-methyl- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)propan-1-one m/z 528/530 (Brisotope) [M + H]+ 249

(S)-2-(4-chloro-3-fluorophenyl)-3- (cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one LCMS (APCI+) m/z 488, 490 [M + H]+ 250

(S)-3-(cyclopropylmethylamino)-2- (3,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 504.3 251

(S)-1-(4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)-2-(4- (triflouromethoxy)phenyl)propan-1- one 550.3 252

(R)-2-(4-chlorophenyl)-3-((3S,5R)- 3,5-dimethylpiperazin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 513.3 253

(R)-2-(4-chlorophenyl)-3-((2S,6R)- 2,6-dimethylmorpholino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 514.3 254

(S)-2-(4-chlorophenyl)-3-((2S,6R)- 2,6-dimethylmorpholino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 514.3 255

(S)-2-(4-chlorophenyl)-3-((3S,5R)- 3,5-dimethylpiperazin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 513.3 256

(S)-2-(3-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4- hydroxypiperidin-1-yl)propan-1-one 552.3 257

(R)-2-(3-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4- hydroxypiperidin-1-yl)propan-1-one 552.3 258

(S)-2-(3-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4- methylpiperazin-1-yl)propan-1-one 551.3 259

(R)-2-(3-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4- methylpiperazin-1-yl)propan-1-one 551.3 260

(S)-2-(3-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4- isopropylpiperazin-1-yl)propan-1-one 579.3261

(R)-2-(3-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4- isopropylpiperazin-1-yl)propan-1-one 579.3262

(S)-3-(cyclopropylmethylamino)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-2-(4-(trifluoromethoxy)phenyl)propan-1- one 520.3 263

(S)-3-amino-2-(4-bromo-3- fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 480.2 264

(S)-3-amino-2-(4-bromo-3- fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 480.1 265

(S)-2-(3,4-dichlorophenyl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 492.3 266

(S)-2-(4-bromo-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one m/z 520, 522 [M + H]+ 267

(S)-2-(4-bromo-3-fluorophenyl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one m/z 520, 522 [M + H]+ 268

(S)-2-(4-bromo-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one m/z562, 564 [M + H]+ 269

(S)-2-(4-bromo-3-fluorophenyl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one m/z562, 564 [M + H]+ 270

(S)-2-(4-bromo-3-fluorophenyl)-3- (cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one m/z 532, 534 [M + H]+ 271

(S)-2-(4-bromo-3-fluorophenyl)-3- (cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one m/z 532, 534 [M + H]+ 272

(S)-2-(3-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one 510.3 273

(S)-2-(4-bromophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one 571.3 274

(S)-2-(4-bromophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one 546.2 275

(S)-3-(cyclopropylmethylamino)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one 504.3 276

(S)-1-(4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)-2-(4- (trifluoromethyl)phenyl)propan-1-one 534.3 277

(S)-3-(cyclopropylmethylamino)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1- (4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)propan-1-one522.3 278

(R)-2-(4-bromo-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one 562.2 279

(S)-2-(4-bromophenyl)-1-(4-((5R,7S)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1- one 518.2 280

(S)-3-amino-2-(4-bromo-2- fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 478.2 281

(S)-3-amino-2-(4-bromo-2- fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 478.2 282

(S)-2-(4-bromophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1- one 443.2 283

(S)-2-(4-bromo-2-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 520.2 284

(S)-2-(4-bromo-2-fluorophenyl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 520.2 285

(S)-3-amino-2-(4-chloro-2- fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 434.2 286

2-(4-chlorophenyl)-3-((3S,4R)-4- (dimethylamino)-3-fluoropiperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)propan-1-one 545.3 287

(S)-2-(4-bromo-2-fluorophenyl)-3- (cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 532.2 288

(S)-3-(tert-butylamino)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one 506.3 289

(S)-2-(3-fluoro-4- (trifluoromethoxy)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one567.6 290

(S)-2-(3-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one552.3 291

(S)-2-(4-chloro-2-fluorophenyl)-3- (cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 488.3 292

(S)-2-(4-bromo-2-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one562.2 293

(S)-2-(4-chloro-2-fluorophenyl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one518.2 294

(S)-2-(4-chloro-2-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one518.3 295

(S)-1-(4-((5R,7S)-7-hydroxy-5- methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)-2-(4- (trifluoromethyl)phenyl)propan-1-one 534.2 296

(S)-3-(cyclopropylmethylamino)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one 504.2 297

(S)-2-(4-bromophenyl)-3-(tert- butylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 516.2 298

(S)-2-(4-chloro-3-fluorophenyl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isobutylamino)propan-1-one m/z 490, 492 [M + H]+ 299

(S)-2-(4-chloro-3-fluorophenyl)-3- (cyclopentylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one m/z 516, 518 [M + H]+ 300

(S)-2-(4-chloro-3-fluorophenyl)-3- (cyclopentylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one m/z 502, 504 [M + H]+ 301

(S)-2-(2-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropyl(methyl)amino)propan-1- one 524.2 302

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-((2-hydroxyethyl)(isopropyl)amino)propan- 1-one 502.3 303

(S)-2-(2-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3- (isopropylamino)propan-1-one 510.2 304

(S)-2-(2-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one552.3 305

(S)-3-amino-2-(2-fluoro-4- (trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 467.2 306

(S)-3-(cyclopropylmethylamino)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1- (4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)propan-1-one552.2 307

(S)-3-(cyclopropylmethylamino)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 538.2 308

(S)-2-(4-bromophenyl)-3-(4,4- dimethylcyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 572.3 309

(S)-2-(4-bromophenyl)-3-(3,3- dimethylcyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 570.3 310

(S)-2-(4-chlorophenyl)-3-(4,4- dimethylcyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 526.4 311

(S)-2-(4-chlorophenyl)-3-(3,3- dimethylcyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 526.3 312

(S)-1-(4-((5R,7R)-7-hydroxy-5- methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)piperazin-1-yl)-3-(isopropylamino)-2-(thiophen-2- yl)propan-1-one 430.3 313

(S)-2-(5-bromothiophen-2-yl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 508.2 314

(S)-2-(5-bromothiophen-2-yl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 508.2 315

(S)-2-(5-bromothiophen-2-yl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one550.2 316

(R)-2-(5-bromopyridin-2-yl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 503.2 317

(S)-2-(5-bromopyridin-2-yl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 503.2 318

(S)-2-(5-bromothiophen-2-yl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one550.2 319

(S)-2-(5-bromothiophen-2-yl)-3- (cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 520.2 320

(S)-2-(5-chlorothiophen-2-yl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one506.2 321

(S)-2-(5-chlorothiophen-2-yl)-1-(4- ((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one 464.2 322

(S)-2-(5-chlorothiophen-2-yl)-1-(4- ((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H- pyran-4-ylamino)propan-1-one506.2 323

(S)-2-(5-chlorothiophen-2-yl)-3- (cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 476.2 324

(S)-2-(5-chlorothiophen-2-yl)-3- (cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one 476.2

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be considered to fall within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groups.

What is claimed is:
 1. A method of inhibiting the activity of AKT protein kinase in a mammal, which comprises contacting said kinase with a compound selected from a compound of Formula I:

and tautomers, resolved enantiomers, resolved diastereomers, and salts thereof, wherein: R¹ is H, Me, Et, vinyl, CF₃, CHF₂ or CH₂F; R² is H or Me; R⁵ is H, Me, Et, or CF₃; A is

G is phenyl optionally substituted by one to four R⁹ groups or a 5-6 membered heteroaryl optionally substituted by a halogen; R⁶ and R⁷ are independently H, OCH₃, (C₃-C₆ cycloalkyl)-(CH₂), (C₃-C₆ cycloalkyl)-(CH₂CH₂), V—(CH₂)₀₋₁ wherein V is a 5-6 membered heteroaryl, W—(CH₂)₁₋₂ wherein W is phenyl optionally substituted with F, Cl, Br, I, OMe, CF₃ or Me, C₃-C₆-cycloalkyl optionally substituted with C₁-C₃ alkyl or O(C₁-C₃ alkyl), hydroxy-(C₃-C₆-cycloalkyl), fluoro-(C₃-C₆-cycloalkyl), CH(CH₃)CH(OH)phenyl, 4-6 membered heterocycle optionally substituted with F, OH, C₁-C₃ alkyl, cyclopropylmethyl or C(═O)(C₁-C₃ alkyl), or C₁-C₆-alkyl optionally substituted with one or more groups independently selected from OH, oxo, O(C₁-C₆-alkyl), CN, F, NH₂, NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂, cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl or tetrahydropyranyl, or R⁶ and R⁷ together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF₃, CH₂CF₃, CH₂CH₂OH, O(C₁-C₃ alkyl), C(═O)CH₃, NH₂, NHMe, N(Me)₂, S(O)₂CH₃, cyclopropylmethyl and C₁-C₃ alkyl; R^(a) and R^(b) are H, or R^(a) is H, and R^(b) and R⁶ together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; R^(c) and R^(d) are H or Me, or R^(c) and R^(d) together with the atom to which they are attached form a cyclopropyl ring; R⁸ is H, Me, F or OH, or R⁸ and R⁶ together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; each R⁹ is independently halogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, O—(C₁-C₆-alkyl), CF₃, OCF₃, S(C₁-C₆-alkyl), CN, OCH₂-phenyl, CH₂O-phenyl, NH₂, NH—(C₁-C₆-alkyl), N—(C₁-C₆-alkyl)₂, piperidine, pyrrolidine, CH₂F, CHF₂, OCH₂F, OCHF₂, OH, SO₂(C₁-C₆-alkyl), C(O)NH₂, C(O)NH(C₁-C₆-alkyl), and C(O)N(C₁-C₆-alkyl)₂; R¹⁰ is H or Me; and m, n and p are independently 0 or
 1. 2. The method of claim 1, wherein A is selected from:


3. The method of claim 1, wherein A is selected from the structures:


4. The method of claim 1 wherein: R¹ is H, Me, Et, CF₃, CHF₂ or CH₂F; R² is H or Me; R⁵ is H, Me, Et, or CF₃; A is

G is phenyl optionally substituted by one to four R⁹ groups; R⁶ and R⁷ are independently H, (C₃-C₆ cycloalkyl)-(CH₂), (C₃-C₆ cycloalkyl)-(CH₂CH₂), V—(CH₂)₀₋₁ wherein V is a 5-6 membered heteroaryl, W—(CH₂)₁₋₂ wherein W is phenyl optionally substituted with F, Cl or Me, C₃-C₆-cycloalkyl, hydroxy-(C₃-C₆-cycloalkyl), fluoro-(C₃-C₆-cycloalkyl), CH(CH₃)CH(OH)phenyl, or C₁-C₆-alkyl optionally substituted with one or more groups independently selected from OH, O(C₁-C₆-alkyl), CN, F, NH₂, NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂, piperidinyl, and pyrrolidinyl, or R⁶ and R⁷ together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF₃, CH₂CF₃, and (C₁-C₃)alkyl; R^(a) and R^(b) are H, or R^(a) is H, and R^(b) and R⁶ together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; R^(c) and R^(d) are H or Me; R⁸ is H, Me, or OH, or R⁸ and R⁶ together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; each R⁹ is independently halogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, O—(C₁-C₆-alkyl), CF₃; OCF₃, S(C₁-C₆-alkyl), CN, CH₂O-phenyl, NH₂, NH—(C₁-C₆-alkyl), N—(C₁-C₆-alkyl)₂, piperidine, pyrrolidine, CH₂F, CHF₂, OCH₂F, OCHF₂, OH, SO₂(C₁-C₆-alkyl), C(O)NH₂, C(O)NH(C₁-C₆-alkyl), and C(O)N(C₁-C₆-alkyl)₂; R¹⁰ is H or Me; and m, n and p are independently 0 or
 1. 5. The method of claim 1 wherein the compound is selected from: 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (R)-2-amino-3-(4-chlorophenyl)-1-((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((5R,7R)-7-methoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one; (S)-3-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-chlorophenyl)-1-((S)-4-((S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one; (2R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((3S)-4-((5R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one; (2R)-2-amino-3-(4-chlorophenyl)-1-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methoxyphenyl)propan-1-one; 2-(4-chlorophenyl)-1-((S)-4-((R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-3-(isopropylamino)propan-1-one; 2-(4-chlorophenyl)-1-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; 2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(7-methoxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; 2-(4-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; 2-(3,4-difluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(pyridin-3-ylmethylamino)propan-1-one; 2-(2,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(pentan-3-ylamino)propan-1-one; 2-(4-chlorophenyl)-3-((1S,2R)-1-hydroxy-1-phenylpropan-2-ylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((1R,4R)-4-hydroxycyclohexylamino)propan-1-one; ((3S,4R)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone; ((3R,4S)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone; 2-(4-chlorophenyl)-2-hydroxy-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; 4-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-methylpentan-1-one; 4-amino-2-(3,4-difluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-methylpentan-1-one; (4-(4-chloro-3-fluorophenyl)piperidin-4-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone; (3-(4-chlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone; 1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-2-p-tolylpropan-1-one; 1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-2-(4-methoxyphenyl)propan-1-one; 3-(ethylamino)-2-(4-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methylamino)propan-1-one; (S)-3-amino-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(pyrrolidin-1-yl)propan-1-one; (R)-2-amino-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-1-((S)-4-((S)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-3-(isopropylamino)propan-1-one; (R)-2-amino-3-(4-chlorophenyl)-1-((S)-4-((R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-4-((R)-7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-1-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (4-(3,4-dichlorophenyl)piperidin-4-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone; 4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone; 1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-methoxyphenyl)-3-(pyrrolidin-1-yl)propan-1-one; 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(2,2,2-trifluoroethylamino)propan-1-one; 3-(tert-butylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)propan-1-one; (S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(5-chlorothiophen-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (R)-2-amino-3-(4-chlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-2-(4-(trifluoromethyl)phenyl)propan-1-one; 4-(1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-1-oxopropan-2-yl)benzonitrile; (S)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; 3-(azetidin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(3-hydroxyazetidin-1-yl)propan-1-one; 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(neopentylamino)propan-1-one; 2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; 2-(4-chlorophenyl)-3-(4-fluoropiperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-3-((S)-3-fluoropyrrolidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-3-(ethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1-one; 2-(4-chlorophenyl)-3-(4,4-difluoropiperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-3-(3,3-difluoropyrrolidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-bromo-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (R)-2-amino-3-(4-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(3,4-dichlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(3,4-difluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-3-((R)-3-fluoropyrrolidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-2-(4-(trifluoromethoxy)phenyl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(cyclopropylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(3-hydroxyazetidin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(3-hydroxyazetidin-1-yl)propan-1-one; (R)-4-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-methylpentan-1-one; (S)-4-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-methylpentan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((R)-pyrrolidin-3-ylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((S)-pyrrolidin-3-ylamino)propan-1-one; (S)-3-((R)-1-acetylpyrrolidin-3-ylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-((S)-1-acetylpyrrolidin-3-ylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(piperidin-4-ylamino)propan-1-one; (S)-3-(1-acetylpiperidin-4-ylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(2-methoxyethylamino)propan-1-one; (R)-2-(4-chlorophenyl)-4-(dimethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((1r,4S)-4-hydroxycyclohexylamino)propan-1-one; (S)-3-(azetidin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-3-(azetidin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylamino)acetamide; 2-((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylamino)-N,N-dimethylacetamide; 2-((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylamino)-N-methylacetamide; (R)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(isopropylamino)butan-1-one; (R)-2-(4-bromophenyl)-4-(dimethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one; (R)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(isobutylamino)butan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-((2-methoxyethyl)(methyl)amino)butan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(isopropylamino)butan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(3-hydroxyazetidin-1-yl)butan-1-one; 2-((R)-3-(4-bromophenyl)-4-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobutylamino)-N,N-dimethylacetamide; (R)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(2-hydroxyethylamino)butan-1-one; (2R)-2-(4-bromophenyl)-4-(2-hydroxy-1-(tetrahydro-2H-pyran-4-yl)ethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one; (R)-2-amino-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-iodophenyl)propan-1-one; 4-((R)-2-amino-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)benzonitrile; (R)-2-amino-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)propan-1-one; (S)-3-(4-acetylpiperazin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-3-(4-acetylpiperazin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(methylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-(2-hydroxyethyl)piperazin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-1-(44(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-(2-hydroxyethyl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(3-methoxyazetidin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-4-(cyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(tetrahydro-2H-pyran-4-ylamino)butan-1-one; (2R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(2-hydroxypropylamino)butan-1-one; (2R)-2-(4-chlorophenyl)-4-(2-hydroxy-1-(tetrahydro-2H-pyran-4-yl)ethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one; (2R)-2-(4-chlorophenyl)-4-(2-hydroxy-1-phenylethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one; (S)-2-(4-chlorophenyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(2-methoxyethylamino)butan-1-one; (2R)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(3,3,3-trifluoro-2-hydroxypropylamino)butan-1-one; (R)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-((1-hydroxycyclopropyl)methylamino)butan-1-one; 2-((R)-3-(4-bromophenyl)-4-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobutylamino)acetamide; (R)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-(tetrahydro-2H-pyran-4-ylamino)butan-1-one; (R)-4-(3-(1H-imidazol-1-yl)propylamino)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-morpholinopropan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-morpholinopropan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one; (S)-3-(3-aminoazetidin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-3-(3-aminoazetidin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-thiomorpholinopropan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(piperazin-1-yl)propan-1-one; (R)-2-(4-chlorophenye-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(piperazin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-thiomorpholinopropan-1-one; (R)-2-(4-chlorophenyl)-3-(4-fluoropiperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(4-fluoropiperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(3-methoxyazetidin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(3-methoxyazetidin-1-yl)propan-1-one; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-3-(dimethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methoxyamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methoxypiperidin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methoxypiperidin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (S)-3-(4-aminopiperidin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-3-(4-aminopiperidin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-(methylsulfonyl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-(methylamino)piperidin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-(methylamino)piperidin-1-yl)propan-1-one; (S)-2-(4-chloro-3-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chloro-3-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (R)-2-(4-chlorophenyl)-3-(4-ethylpiperazin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(4-ethylpiperazin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-3-((S)-3-(dimethylamino)pyrrolidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-((S)-3-(dimethylamino)pyrrolidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((R)-tetrahydrofuran-3-ylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((R)-tetrahydrofuran-3-ylamino)propan-1-one; (S)-2-(4-chlorophenyl)-3-(2-fluoroethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-fluoro-3-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(3,5-bis(trifluoromethyl)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(3-fluoro-4-methoxyphenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; 4-((R)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)piperazin-2-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((R)-3-hydroxypyrrolidin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(4-(dimethylamino)piperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-3-(4-(dimethylamino)piperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(3-chloro-5-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(3-bromo-4-methoxyphenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(piperidin-4-ylamino)propan-1-one; (R)-2-(1-acetylpiperidin-4-ylamino)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-((R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylamino)-N-isopropylacetamide; (R)-3-(4-chlorophenyl)-2-(dimethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(2-morpholinoethylamino)propan-1-one; (R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(isopropylamino)propan-1-one; (R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (R)-3-(4-chlorophenyl)-1-((S)-4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-(isopropylamino)propan-1-one; 2-((R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylamino)-N,N-dimethylacetamide; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(1,4-oxazepan-4-yl)propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(1,4-oxazepan-4-yl)propan-1-one; (R)-2-(4-chloro-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chloro-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-3-(cyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(cyclohexylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methoxycyclohexylamino)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((S)-tetrahydrofuran-3-ylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methyltetrahydro-2H-pyran-4-ylamino)propan-1-one; (R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)propan-1-one; (R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(3,3,3-trifluoropropylamino)propan-1-one; (R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl)methylamino)propan-1-one; (R)-3-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(isopropyl(methyl)amino)propan-1-one; (S)-3-(tert-butylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-3-(tert-butylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one; (R)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (R)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-morpholinopropan-1-one; (R)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one; (R)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one; (S)-3-(cyclopropylmethylamino)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-(cyclopropylmethylamino)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-2-(4-(trifluoromethyl)phenyl)propan-1-one; (S)-3-amino-2-(4-bromophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-amino-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; 3-((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylamino)propanamide; 3-((S)-2-(4-chlorophenyl)-3-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylamino)propanamide; (4-(4-chlorophenyl)piperidin-4-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone; (S)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-3-amino-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-amino-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-3-amino-2-(3,4-dichlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (R)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one; (S)-2-(3,5-difluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-3-((R)-3-aminopyrrolidin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-3-((R)-3-aminopyrrolidin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-morpholinopropan-1-one; (R)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-morpholinopropan-1-one; (S)-3-(4-ethylpiperazin-1-yl)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-3-(4-ethylpiperazin-1-yl)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-(4-acetylpiperazin-1-yl)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-3-(4-acetylpiperazin-1-yl)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-(bis(cyclopropylmethyl)amino)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-bromophenyl)-3-((cyclopropylmethyl)(methyl)amino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-(cyclopropylmethylamino)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)-2-(4-(trifluoromethoxy)phenyl)propan-1-one; (R)-2-(4-chlorophenyl)-3-((3S,5R)-3,5-dimethylpiperazin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-3-((2S,6R)-2,6-dimethylmorpholino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-((2S,6R)-2,6-dimethylmorpholino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-((3S,5R)-3,5-dimethylpiperazin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one; (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methylpiperazin-1-yl)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one; (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one; (S)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-(trifluoromethoxy)phenyl)propan-1-one; (S)-3-amino-2-(4-bromo-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-amino-2-(4-bromo-3-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-bromo-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-bromo-3-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-bromo-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-bromo-3-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-bromo-3-fluorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromo-3-fluorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (S)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one; (S)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)-2-(4-(trifluoromethyl)phenyl)propan-1-one; (S)-3-(cyclopropylmethylamino)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-(4-bromo-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1-one; (S)-3-amino-2-(4-bromo-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-amino-2-(4-bromo-2-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1-one; (S)-2-(4-bromo-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-bromo-2-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-3-amino-2-(4-chloro-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-3-((3S,4R)-4-(dimethylamino)-3-fluoropiperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromo-2-fluorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-(tert-butylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-chloro-2-fluorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromo-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-chloro-2-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-chloro-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)-2-(4-(trifluoromethyl)phenyl)propan-1-one; (S)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one; (S)-2-(4-bromophenyl)-3-(tert-butylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isobutylamino)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-3-(cyclopentylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-3-(cyclopentylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((2-hydroxyethyl)(isopropyl)amino)propan-1-one; (S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-3-amino-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-(cyclopropylmethylamino)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-(cyclopropylmethylamino)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-3-(4,4-dimethylcyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-3-(3,3-dimethylcyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(4,4-dimethylcyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(3,3-dimethylcyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-2-(thiophen-2-yl)propan-1-one; (S)-2-(5-bromothiophen-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(5-bromothiophen-2-yl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(5-bromothiophen-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (R)-2-(5-bromopyridin-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(5-bromopyridin-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(5-bromothiophen-2-yl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(5-bromothiophen-2-yl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(5-chlorothiophen-2-yl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(5-chlorothiophen-2-yl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(5-chlorothiophen-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(5-chlorothiophen-2-yl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; and (S)-2-(5-chlorothiophen-2-yl)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; and salts thereof.
 6. The method of claim 1 wherein the compound is selected from a compound of Formula IB:

resolved enantiomers, resolved diastereomers, and salts thereof, wherein: G is phenyl optionally substituted by one to four R⁹ groups or a 5-6 membered heteroaryl optionally substituted by a halogen; R⁶ and R⁷ are independently H, OCH₃, (C₃-C₆ cycloalkyl)-(CH₂), (C₃-C₆ cycloalkyl)-(CH₂CH₂), V—(CH₂)₀₋₁ wherein V is a 5-6 membered heteroaryl, W—(CH₂)₁₋₂ wherein W is phenyl optionally substituted with F, Cl, Br, I, OMe, CF₃ or Me, C₃-C₆-cycloalkyl optionally substituted with C₁-C₃ alkyl or O(C₁-C₃ alkyl), hydroxy-(C₃-C₆-cycloalkyl), fluoro-(C₃-C₆-cycloalkyl), CH(CH₃)CH(OH)phenyl, 4-6 membered heterocycle optionally substituted with F, OH, C₁-C₃ alkyl, cyclopropylmethyl or C(═O)(C₁-C₃ alkyl), or C₁-C₆-alkyl optionally substituted with one or more groups independently selected from OH, oxo, O(C₁-C₆-alkyl), CN, F, NH₂, NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂, cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl or tetrahydropyranyl, or R⁶ and R⁷ together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF₃, CH₂CF₃, CH₂CH₂OH, O(C₁-C₃ alkyl), C(═O)CH₃, NH₂, NHMe, N(Me)₂, S(O)₂CH₃, cyclopropylmethyl and C₁-C₃ alkyl; and each R⁹ is independently halogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, O—(C₁-C₆-alkyl), CF₃, OCF₃, S(C₁-C₆-alkyl), CN, OCH₂-phenyl, CH₂O-phenyl, NH₂, NH—(C₁-C₆-alkyl), N—(C₁-C₆-alkyl)₂, piperidine, pyrrolidine, CH₂F, CHF₂, OCH₂F, OCHF₂, OH, SO₂(C₁-C₆-alkyl), C(O)NH₂, C(O)NH(C₁-C₆-alkyl), and C(O)N(C₁-C₆-alkyl)₂.
 7. The method of claim 6, wherein G is phenyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, Me, ethyl, isopropyl, CN, CF₃, OCF₃, SMe, OMe and OCH₂Ph.
 8. The method of claim 6, wherein G is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-thiomethylphenyl, 4-trifluoromethoxyphenyl, 4-cyclopropylphenyl, 4-chloro-3-fluorophenyl, 3,4-difluorophenyl, 4-bromo-3-fluorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-bromophenyl, 3-fluoro-4-trifluoromethylphenyl, 4-cyano-3-fluorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl, 3-bromo-4-fluorophenyl, 3,5-difluoro-4-chlorophenyl, 2,3-difluoro-4-chlorophenyl, 2,5-difluoro-4-chlorophenyl, 3,5-difluoro-4-bromophenyl, 2,3-difluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl or 4-(OCH₂Ph)-phenyl.
 9. The method of claim 8, wherein G is 4-chlorophenyl, 2,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl, 3-fluoro-4-bromophenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-thiomethylphenyl, or 4-methylphenyl.
 10. The method of claim 6, wherein G is a thiophene or pyridine optionally substituted by a halogen.
 11. The method of claim 10, wherein G is selected from the structures:


12. The method of claim 6, wherein R⁶ and R⁷ are independently selected from H, OCH₃, (C₃-C₆ cycloalkyl)-(CH₂), (C₃-C₆ cycloalkyl)-(CH₂CH₂), V—(CH₂)₀₋₁ wherein V is a 5-6 membered heteroaryl having from one to two ring heteroatoms independently selected from N, O and S, W—(CH₂)₁₋₂ wherein W is phenyl optionally substituted with F, Cl or Me, C₃-C₆-cycloalkyl optionally substituted with OCH₃, hydroxy-(C₃-C₆-cycloalkyl), fluoro-(C₃-C₆-cycloalkyl), CH(CH₃)CH(OH)phenyl, 5-6 membered heterocycle optionally substituted with CH₃ or C(═O)CH₃, or C₁-C₆-alkyl optionally substituted with one or more groups independently selected from OH, oxo, O(C₁-C₆-alkyl), CN, F, NH₂, NH(C₁-C₆-alkyl), N(C₁-C₆-alkyl)₂, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, and tetrahydropyranyl.
 13. The method of claim 1, wherein R⁶ and R⁷ are independently selected from H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, 3-pentyl, OCH₃, CH₂CH₂OH, CH₂CH₂OMe, CH₂CH₂CF₃, CH₂CH(CH₃)OH, CH₂CH(CF₃)OH, CH₂CF₃, CH₂CH₂F, CH₂C(═O)NH₂, CH₂C(═O)NH(CH₃), CH₂C(═O)N(CH₃)₂, CH₂C(═O)NH(iPr), CH₂CH₂C(═O)NH₂, CH₂-cyclopropyl, CH₂-cyclopentyl, CH₂-tBu (neopentyl), cyclopropyl, cyclopentyl, cyclohexyl, 4-methoxycyclohexyl, 4,4-dimethylcyclohexyl, 3,3-dimethylcyclohexyl, CH₂-(pyrid-3-yl), 4-hydroxycyclohex-1-yl, CH(CH₃)CH(OH)phenyl, CH(phenyl)CH₂OH, CH(tetrahydropyranyl)CH₂OH, CH₂CH₂CH₂(imidazolyl), CH₂CH₂(morpholinyl), CH₂(tetrahydropyranyl), CH₂CH₂(tetrahydropyranyl), pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl,


14. The method of claim 6, wherein R⁶ and R⁷ together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF₃, CH₂CF₃, CH₂CH₂OH, OCH₃, C(═O)CH₃, NH₂, NHMe, N(Me)₂, S(O)₂CH₃, and (C₁-C₃)alkyl.
 15. The method of claim 14, wherein NR⁶R⁷ is selected from the structures:


16. The method of claim 6, wherein NR⁶R⁷ is NH₂, NHMe, NHEt, NHPr, NHiPr, NHtBu, NH(CH₂-tBu), NH(CH₂-cyclopropyl), NH(CH₂-cyclobutyl), NH(cyclopentyl), NH(CH₂-pyridyl), NH(cyclohexyl), NH(3-pentyl), NH(CH₂CH₂OH), NH(CH₂CH₂CH₂OH), NH(CH₂CH₂OMe), NH(CH₂CH₂CH₂OMe), NH(CH₂CN), NMe₂, NMeEt, NMePr, NMe(iPr), NMe(CH₂-cyclopropyl), NMe(CH₂-cyclobutyl), NMe(CH₂CH₂OH), NMe(CH₂CH₂CH₂OH), NMe(CH₂CH₂OMe), NMe(CH₂CH₂CH₂OMe), NEt₂, NEtPr, NEt(iPr), NEt(CH₂-cyclopropyl), NEt(CH₂-cyclobutyl), NEt(CH₂CH₂OH), NEt(CH₂CH₂CH₂OH),


17. The method of claim 1 wherein the compound is selected from: (S)-3-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-3-amino-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)propan-1-one; (S)-2-(5-chlorothiophen-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-2-(4-(trifluoromethoxy)phenyl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(cyclopropylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(3-hydroxyazetidin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((R)-pyrrolidin-3-ylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((S)-pyrrolidin-3-ylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-thiomorpholinopropan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(4-fluoropiperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(3-methoxyazetidin-1-yl)propan-1-one; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-3-(dimethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methoxyamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methoxypiperidin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (S)-3-(4-aminopiperidin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-(methylamino)piperidin-1-yl)propan-1-one; (S)-2-(4-chloro-3-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chloro-3-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-3-(4-ethylpiperazin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-((S)-3-(dimethylamino)pyrrolidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((R)-tetrahydrofuran-3-ylamino)propan-1-one; (S)-2-(4-chlorophenyl)-3-(2-fluoroethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-fluoro-3-(trifluoromethoxy)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(3-fluoro-4-methoxyphenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-3-(4-(dimethylamino)piperidin-1-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(3-chloro-5-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(3-bromo-4-methoxyphenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(1,4-oxazepan-4-yl)propan-1-one; (S)-2-(4-chloro-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-3-(cyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one; (S)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one; (S)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)-2-(4-(trifluoromethyl)phenyl)propan-1-one; (S)-3-(cyclopropylmethylamino)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-amino-2-(4-bromo-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1-one; (S)-2-(4-bromo-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-3-amino-2-(4-chloro-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-(tert-butylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one; (S)-2-(4-chloro-2-fluorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromo-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-chloro-2-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-bromophenyl)-3-(tert-butylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isobutylamino)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-3-(cyclopentylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-3-(cyclopentylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((2-hydroxyethyl)(isopropyl)amino)propan-1-one; (S)-3-amino-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-3-(4,4-dimethylcyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-bromophenyl)-3-(3,3-dimethylcyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(4,4-dimethylcyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(3,3-dimethylcyclohexylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-2-(thiophen-2-yl)propan-1-one; (S)-2-(5-bromothiophen-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(5-bromothiophen-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (R)-2-(5-bromopyridin-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(5-bromothiophen-2-yl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(5-chlorothiophen-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; and (S)-2-(5-chlorothiophen-2-yl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; and salts thereof.
 18. The method of claim 1 wherein the compound is selected from (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one and salts thereof.
 19. The method of claim 1 wherein the compound is selected from (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)propan-1-one and salts thereof.
 20. The method of claim 1 wherein the compound is selected from (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(3-hydroxyazetidin-1-yl)propan-1-one and salts thereof.
 21. The method of claim 1 wherein the compound is selected from (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((R)-pyrrolidin-3-ylamino)propan-1-one and salts thereof.
 22. The method of claim 1 wherein the compound is selected from (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((S)-pyrrolidin-3-ylamino)propan-1-one and salts thereof.
 23. The method of claim 1 wherein the compound is selected from (S)-3-(1-acetylpiperidin-4-ylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one and salts thereof.
 24. The method of claim 1 wherein the compound is selected from (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one and salts thereof.
 25. The method of claim 1 wherein the compound is selected from (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one and salts thereof.
 26. The method of claim 1 wherein the compound is selected from (S)-2-(4-chlorophenyl)-3-(dimethylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one and salts thereof.
 27. The method of claim 1 wherein the compound is selected from (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropyl(methyl)amino)propan-1-one and salts thereof.
 28. The method of claim 1 wherein the compound is selected from (S)-2-(4-chloro-3-(trifluoromethyl)phenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one and salts thereof.
 29. The method of claim 1 wherein the compound is selected from (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-methoxycyclohexylamino)propan-1-one and salts thereof.
 30. The method of claim 1 wherein the compound is selected from (S)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one and salts thereof.
 31. The method of claim 1 wherein the compound is selected from (S)-3-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one and salts thereof.
 32. The method of claim 1 wherein the compound is selected from (S)-3-(tert-butylamino)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one and salts thereof.
 33. The method of claim 1, wherein said mammal is suffering a disease or disorder selected from an inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynecological, or dermatological disease or disorder. 